WO2015164604A1 - Inhibiteurs de janus kinase marqués de manière hydrophobe et utilisations associées - Google Patents

Inhibiteurs de janus kinase marqués de manière hydrophobe et utilisations associées Download PDF

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WO2015164604A1
WO2015164604A1 PCT/US2015/027294 US2015027294W WO2015164604A1 WO 2015164604 A1 WO2015164604 A1 WO 2015164604A1 US 2015027294 W US2015027294 W US 2015027294W WO 2015164604 A1 WO2015164604 A1 WO 2015164604A1
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substituted
unsubstituted
certain embodiments
formula
instance
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Nathanael Gray
Li Tan
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Dana-Farber Cancer Institute, Inc.
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Priority to US15/305,845 priority Critical patent/US9862688B2/en
Publication of WO2015164604A1 publication Critical patent/WO2015164604A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • JAK inhibitors are rapidly becoming one of the most validated and pursued class of drug targets.
  • Janus kinases comprise a family of 4 kinases that play multiple roles downstream of cytokine signalling in both immune and non-immune cells. Autoimmunity is driven by an aberrant adaptive immune response to self-antigens and JAK-STAT signalling is known to play a key role in this process.
  • JAK inhibitors have considerable potential for the development of drugs to treat autoimmunity.
  • JAK3 is an especially attractive target as, unlike other JAKs, its expression is restricted to the immune system.
  • Several pharmaceutical companies have considerable efforts underway to develop JAK3 inhibitors.
  • pan- JAK inhibitors While the FDA recently approved the JAK3 inhibitor Tofacitnib (XELJANZ ® ), which is actually a pan- JAK inhibitor, it was rejected by CHMP in Europe due to safety concerns. This highlights the fact that while pan- JAK inhibitors are effective in RA, they carry a range of adverse side effects, many of which may relate to the functions of JAKs outside the adaptive immune system. Therefore, development of selective small molecule inhibitors of JAK3 would potentially represent a promising class of novel therapeutics.
  • hydrophobic tags used to induce protein degradation may eventually be found useful in a variety of applications, such as, for example, tagged therapeutic agents and tagged research tools for inducing protein degradatation in vivo and in vitro.
  • hydrophobically tagged agents and tools is underrealized and continues to remain of great interest.
  • the present invention is based on the development of kinase inhibitors, such as the compounds described herein (i.e., compounds of Formula (I) and (II)).
  • the compounds described herein possess a kinase recognition element that binds the kinase either covalently or non-covalently.
  • the compounds described herein are further "tagged" with a hydrophobic moiety R . While the precise function of these hydrophobic moeties are unknown, it has been observed that such functionality can lead to improved bioactivity through mechanisms not directly associated with enzymatic inhibition.
  • R G , R J1 , R J2 , R z , Wi, W 2 , W 3 , R Y1 , R Y2 , a, k, y, and x are as described herein.
  • the kinase inhibitors of Formula (I) or (II) inhibit JAK, e.g., JAKl, JAK2, JAK3, or TYK2. In certain aspects, the kinase inhibitors of Formula (I) or (II) inhibit JAK3. In certain aspects, the kinase inhibitors of Formula (I) or (II) inhibit JAK3 selectively. In certain aspects, the kinase inhibitors of Formula (I) or (II) inhibit JAK3 up to 100-fold selectively over JAKl and/or JAK2, which do not possess an equivalently placed cysteine residue.
  • the kinase inhibitors of Formula (I) or (II) inhibit EGFR. In certain aspects, the kinase inhibitors of Formula (I) or (II) inhibit a gatekeeper mutant (T790M) of EGFR.
  • the compounds described herein comprises group of formula
  • a compound of Formula (I) or (II) is a double bond, wherein such group in certain embodiments covalently reacts with and/or binds to the kinase.
  • the compounds describe herein comprises a
  • compositions comprising a compound of Formula (I) or (II) and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may be useful for reducing the activity of a kinase in a subject in need thereof, and/or for treating and/or preventing in a subject in need thereof a condition associated with aberrant activity of a kinase (e.g., a proliferative disease, inflammatory disorder, autoimmune disorder, painful condition, or viral infection).
  • a condition associated with aberrant activity of a kinase e.g., a proliferative disease, inflammatory disorder, autoimmune disorder, painful condition, or viral infection.
  • methods for reducing the activity of a kinase in a subject in need thereof includes administering to the subject a compound described herein, or a pharmaceutical composition thereof, in an amount sufficient to reduce the activity of the kinase.
  • a condition associated with aberrant activity of a kinase e.g., a proliferative disease, inflammatory disorder, autoimmune disorder, painful condition, or viral infection.
  • the method includes administering to the subject a compound described herein, or a pharmaceutical composition thereof, in an amount sufficient to treat and/or prevent the condition.
  • kits comprising a container with a compound described herein, or a pharmaceutical composition thereof.
  • the kits may include a single dose or multiple doses of a compound described herein or a pharmaceutical composition thereof.
  • the kits may be useful for reducing the activity of a kinase in a subject in need thereof.
  • the kits may also be useful for treating and/or preventing in a subject in need thereof a condition associated with aberrant activity of a kinase.
  • the kits further include instructions for using the kit (e.g., for administering a compound described herein, or a pharmaceutical composition thereof).
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Racemic refers to a compound in which the percent by weight of one enantiomer is equal to the percent by weight of the other enantiomer.
  • enantiomerically enriched refers to a compound in which the percent by weight of one enantiomer is greater than the amount of that one enantiomer compared to a control mixture of the racemic composition (e.g., greater than 1: 1 by weight).
  • a control mixture of the racemic composition e.g., greater than 1: 1 by weight.
  • enantiomerically enriched enantiomer means a compound having greater than 50% by weight of one enantiomer relative to the other enantiomer, e.g., at least 75% by weight, or at least 80% by weight. In some embodiments, the enrichment can be much greater than 80% by weight, providing a "substantially enantiomerically enriched," "substantially
  • enantiomerically pure or a "substantially non-racemic” compound, which refers to a compound with at least 85% by weight of one enantiomer relative to other enantiomer, e.g., at least 90% by weight, or at least 95% by weight.
  • Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, et ah, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et ah, Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of the disclosure.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • C ⁇ alkyl is intended to encompass, C 1; C 2 , C 3 , C 4 , C 5 , C 6 , Ci-6, Ci-5, Ci ⁇ , Ci-3, Ci-2, C 2 -6, C 2 _5, C 2 ⁇ , C 2 _3, C 3 _ 6 , C 3 _ 5 , C 3 ⁇ , C ⁇ , C 4 _ 5 , and C 5 _6 alkyl.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C ⁇ o alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“Q-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("Ci_g alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“Ci-j alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C ⁇ s alkyl”).
  • an alkyl group has 1 to 4 carbon atoms ("C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“Ci_ 3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("Ci-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Q alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 -6 alkyl”).
  • C ⁇ alkyl groups include methyl (CO, ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (Cg) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents. In certain embodiments, the alkyl group is an unsubstituted C ⁇ o alkyl (e.g., -CH 3 ). In certain embodiments, the alkyl group is a substituted C o alkyl.
  • haloalkyl is a substituted alkyl group as described herein wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • a halogen e.g., fluoro, bromo, chloro, or iodo.
  • Perhaloalkyl is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 8 carbon atoms ("Ci_g haloalkyl").
  • the haloalkyl moiety has 1 to 6 carbon atoms ("C ⁇ haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C ⁇ haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C ⁇ haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("Ci_ 2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group.
  • haloalkyl hydrogen atoms are replaced with chloro to provide a "perchloroalkyl" group.
  • haloalkyl groups include -CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CCI 3 , -CFC1 2 , -CF 2 C1, and the like.
  • heteroalkyl refers to an alkyl group as described herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroCi-io alkyl").
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4
  • heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroCi-g alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroCi-7 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms within the parent chain (“heteroCi-6 alkyl").
  • a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCi-s alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain ("heteroCi ⁇ alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain
  • heteroCi-s alkyl a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain ("heteroC ⁇ alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2 -6 alkyl").
  • each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl”) with one or more substituents.
  • the heteroalkyl group is an
  • the heteroalkyl group is a substituted heteroCi-io alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more double bonds (e.g., 1, 2, 3, or 4 double bonds).
  • an alkenyl group has 2 to 9 carbon atoms ("C 2 -9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms ("C 2 -8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C 2 _ 7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2 -6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms ("C 2 _5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2 _4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2 _ 3 alkenyl”). In some
  • an alkenyl group has 2 carbon atoms ("C 2 alkenyl").
  • the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2 - alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • C 2 _6 alkenyl groups include the aforementioned C 2 ⁇ alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (Cg), octatrienyl (Cg), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a
  • substituted alkenyl with one or more substituents.
  • the alkenyl group is an unsubstituted C 2 _ 10 alkenyl.
  • the alkenyl group is a substituted C 2 _io alkenyl.
  • heteroalkenyl refers to an alkenyl group as described herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC ⁇ io alkenyl").
  • a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroC 2 _9 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC 2 _g alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC 2 _7 alkenyl").
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms within the parent chain ("heteroC 2 _6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2
  • heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms within the parent chain ("heteroC 2 ⁇ alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2 _ 3 alkenyl”).
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2 _6 alkenyl").
  • each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents.
  • the heteroalkenyl group is an unsubstituted heteroC 2 -io alkenyl.
  • the heteroalkenyl group is a substituted heteroC 2 -io alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more triple bonds (e.g., 1, 2, 3, or 4 triple bonds) and optionally one or more double bonds (e.g., 1, 2, 3, or 4 double bonds) ("C 2 -io alkynyl").
  • an alkynyl group has 2 to 9 carbon atoms ("C 2 -9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2 -8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms (“C 2 _ 7 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms ("C 2 -6 alkynyl").
  • an alkynyl group has 2 to 5 carbon atoms ("C 2 _5 alkynyl").
  • an alkynyl group has 2 to 4 carbon atoms ("C 2 ⁇ alkynyl").
  • an alkynyl group has 2 to 3 carbon atoms ("C 2 - 3 alkynyl").
  • an alkynyl group has 2 carbon atoms ("C 2 alkynyl").
  • the one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2 - alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • C 2 -6 alkenyl groups include the aforementioned C 2 - alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (Cg), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 2 -io alkynyl. In certain embodiments, the alkynyl group is a substituted C 2 _ 10 alkynyl.
  • heteroalkynyl refers to an alkynyl group as described herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC 2 -io alkynyl").
  • a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 , 2, 3, or 4 heteroatoms within the parent chain ("heteroC 2 -9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 , 2, 3, or 4 heteroatoms within the parent chain ("heteroC 2 - 8 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC 2 -7 alkynyl").
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 , 2, or 3 heteroatoms within the parent chain ("heteroC 2 -6 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -5 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain ("heteroC 2 - alkynyl").
  • a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("heteroC 2 - 3 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -6 alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC 2 io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-io alkynyl.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C 3 _ 14 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms (" ⁇ 3 _ 10 carbocyclyl”).
  • a carbocyclyl group has 3 to 9 ring carbon atoms ("C 3 _g carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3 _ 8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3 _7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3 _6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io carbocyclyl”).
  • Exemplary C 3 _ 6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3 _ 8 carbocyclyl groups include, without limitation, the aforementioned C 3 _ 6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3 _io carbocyclyl groups include, without limitation, the aforementioned C 3 _ 8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro-fused ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • exemplary fused bicyclic systems include, but are not limited to, decalin (cis or trans decalin).
  • Exemplary fused tricyclic systems include, but are not limited to, fluorenyl.
  • Exemplary spiro-fused bicyclic systems include, but are not limited to, spiropentane.
  • Exemplary bridged bicyclic systems include, but are not limited to, norbornane, norbornene, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, bicyclo[3.2.1]octane, and bicyclo[2.2.1]heptan-2-one.
  • Exemplary bridged tricyclic systems include, but are not limited to adamantane.
  • Carbocyclyl includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted
  • carbocyclyl or substituted (a "substituted carbocyclyl") with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3 _ 14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3 _ 14 carbocyclyl.
  • Carbocyclylalkyl is a subset of “alkyl” and refers to an alkyl group, as described herein, substituted by an carbocyclyl group, as described herein, wherein the point of attachment is on the alkyl moiety.
  • heterocyclyl refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl").
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • the heterocyclyl group is either monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro-fused ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)) and can be saturated or can contain one or more carbon- carbon double or triple bonds.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
  • Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,
  • Heterocyclylalkyl is a subset of “alkyl” and refers to an alkyl group, as described herein, substituted by one or more heterocyclyl groups, as described herein, wherein the point of attachment is on the alkyl moiety.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-i 4 aryl").
  • an aryl group has 6 ring carbon atoms ("C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms ("Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms ("C 14 aryl”; e.g., anthracenyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is
  • the aryl group is an unsubstituted 14 aryl. In certain embodiments, the aryl group is a substituted Ce_ 14 aryl.
  • alkyl or "arylalkyl” is a subset of “alkyl” and refers to an alkyl group, as described herein, substituted by one or more aryl groups, as described herein, wherein the point of attachment is on the alkyl moiety.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an
  • heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • 5- membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • 6- membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
  • Heteroaralkyl or “heteroarylalkyl” is a subset of “alkyl” and refers to an alkyl group, as described herein, substituted by one or more heteroaryl groups, as described herein, wherein the point of attachment is on the alkyl moiety.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties) as herein defined.
  • saturated refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as described herein, are, in certain embodiments, optionally substituted.
  • Optionally substituted refers to a group which may be substituted or unsubstituted ⁇ e.g., "substituted” or "unsubstituted” alkyl, "substituted” or “unsubstituted” alkenyl, "substituted” or “unsubstituted” alkynyl, "substituted” or
  • substituted means that at least one hydrogen present on a group ⁇ e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted" group has a substituent at one or more
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • R ⁇ is, independently, selected from C ⁇ o alkyl, C ⁇ o perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, C ⁇ o heteroalkyl, C 2 _io heteroalkenyl, C ⁇ ioheteroalkynyl, C 3 _ 14 carbocyclyl, 3-14 membered heterocyclyl, C 6 -i 4 aryl, and 5-14 membered heteroaryl, or two R ⁇ groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl,
  • each instance of R cc is, independently, selected from hydrogen, C ⁇ o alkyl, C ⁇ o perhaloalkyl, C 2 _ 10 alkenyl, C 2 _ 10 alkynyl, d-io heteroalkyl, C 2 _ 10 heteroalkenyl, C 2
  • heteroalkynyl C 3 _ 14 carbocyclyl, 3-14 membered heterocyclyl, -i 4 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from d_6 alkyl, d_6 perhaloalkyl, C 2 6 alkenyl, C 2 _ 6 alkynyl, d_ 6 heteroalkyl, C 2 _ 6 heteroalkenyl, C 2 _ 6 heteroalkynyl, C 3 _io
  • each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R ff is, independently, selected from hydrogen, d_ 6 alkyl, d_ 6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, d_6 heteroalkyl, C 2 _ 6 heteroalkenyl, C 2
  • halo refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I).
  • counterion is a negatively charged group associated with a positively charged quarternary amine in order to maintain electronic neutrality.
  • exemplary counterions include halide ions (e.g., , CF, Br " , ⁇ ), N0 3 , C10 4 , OH , H 2 P0 4 , HS0 4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10- camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate,
  • hydroxyl refers to the group -OH.
  • thiol refers to the group -SH.
  • amino refers to the group -NH 2 .
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino, as described herein. In certain embodiments, the "substituted amino” is a monosubstituted amino or a disubstituted amino group.
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(R bb ) 3 and -N(R bb ) 3 + X ⁇ , wherein R bb and X " are as described herein.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
  • the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an "amino protecting group").
  • heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , R cc and R dd are as described herein.
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G.
  • TBOC l-methyl-l-(4-biphenylyl)ethyl carbamate
  • Bpoc l-(3,5-di-/-butylphenyl)-l- methylethyl carbamate
  • i-Bumeoc 2-(2'- and 4'-pyridyl)ethyl carbamate
  • Pyoc 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, /-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carb
  • Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5, 6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7, 8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)- acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl- 3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-l, l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl- l,3,5-triazacyclohexan-2-one, 5-
  • benzenesulfenamide o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,
  • triphenylmethylsulfenamide triphenylmethylsulfenamide
  • 3-nitropyridinesulfenamide Npys
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an "hydroxyl protecting group").
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
  • DPMS diphenylmethylsilyl
  • TMPS i-butylmethoxyphenylsilyl
  • dimethylphosphinothioyl dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).
  • the substituent present on an sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group").
  • Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. , describes pharmaceutically acceptable salts in detail in /. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • a "subject" to which administration is contemplated includes, but is not limited to, humans ⁇ i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other non-human animals, for example, mammals (e.g. , primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs), birds (e.g.
  • mammals e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs), birds (e.g.
  • the non-human animal is a mammal.
  • the non-human animal may be a male or female and at any stage of development.
  • a non-human animal may be a transgenic animal.
  • treat contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition ("prophylactic treatment").
  • the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response.
  • the effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • a therapeutically effective amount of a compound refers to an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • the condition is associated with aberrant activity of a kinase (e.g. , JAK3).
  • a therapeutically effective amount is an amount sufficient to reduce the activity or expression of a kinase (e.g. , JAK3)and/or inhibit cell proliferation.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • inhibitor refers to the ability of a compound to reduce (e.g., slow, halt) or prevent activity of a particular biological process (kinase activity) in a cell relative to vehicle.
  • At least one instance refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g. , for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
  • a "kinase” is a type of enzyme that transfers phosphate groups from high energy donor molecules, such as ATP, to specific substrates, referred to as phosphorylation.
  • Kinases are part of the larger family of phosphotransferases.
  • One of the largest groups of kinases are protein kinases, which act on and modify the activity of specific proteins.
  • Kinases are used extensively to transmit signals and control complex processes in cells.
  • Various other kinases act on small molecules such as lipids, carbohydrates, amino acids, and nucleotides, either for signaling or to prime them for metabolic pathways.
  • Kinases are often named after their substrates. More than 500 different protein kinases have been identified in humans.
  • exemplary human protein kinases include, but are not limited to, AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1, AKT2, AKT3, ALK, ALK1, ALK2, ALK4, ALK7, AMPKal, AMPKa2, ANKRD3, ANPa, ANPb, ARAF, ARAFps, ARG, AurA, AurApsl, AurAps2, AurB, AurBpsl, AurC, AXL, BARK1, BARK2, BIKE, BLK, BMPR1A, BMPRlApsl, BMPRlAps2, BMPR1B, BMPR2, BMX, BRAF, BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMKla, CaMKlb, CaMKld, CaMKlg, CaMK2a, CaMK2b, CaMK2d, CaMK2
  • PITSLRE PKACa, PKACb, PKACg, PKCa, PKCb, PKCd, PKCe, PKCg, PKCh, PKCi, PKCips, PKCt, PKCz, PKD1, PKD2, PKD3, PKG1, PKG2, PKN1, PKN2, PKN3, PKR, PLK1, PLKlpsl, PLKlps2, PLK2, PLK3, PLK4, PRKX, PRKXps, PRKY, PRP4, PRP4ps, PRPK, PSKH1, PSKHlps, PSKH2, PYK2, QIK, QSK, RAF1, RAFlps, RET, RHOK, RIPK1, RIPK2, RIPK3, RNAseL, ROCK1, ROCK2, RON, ROR1, ROR2, ROS, RSK1, RSK12, RSK2, RSK22, RSK3, RSK32, RSK4, RSK42, RSKL1,
  • the kinase is JAK3 kinase.
  • inhibitors possessing the ability to covalently modify JAK3 developed which include a hydrophobic tag moiety (R ) to enhance the bioactivity of the JAK3 inhibitors. While the precise function of these hydrophobic moeties are unknown, it has been observed that such functionality can lead to improved bioactivity through mechanisms not directly associated with enzymatic inhibition.
  • non-covalent analogs were also discovered (e.g. , reduced acrylamide moiety) and likewise modified with hydrophobic tags. These non-covalent derivatives could serve as complementary therapeutics that exhibit alternate modes of inhibition and pharmacokinetic/pharmacodynamic profiles.
  • JAK inhibitors e.g., which may inhibit JAK (e.g., JAK3 selectively:
  • Wi is N, W 2 is N and W 3 is CR , or Wi is N W 2 is CH, and W 3 is N;
  • R are each a group of formula or - -R H ; is selected from the roup consisting of:
  • t is 2, 3, 4, 5, or 6;
  • L is a bond or a linker selected from the group consisting of substituted and unsubstituted Ci ⁇ alkylene, substituted and unsubstituted C 2 - 6 alkenylene, substituted and unsubstituted C 2 - 6 alkynylene, substituted and unsubstituted heteroCi-ealkylene, substituted and unsubstituted heteroC 2 - 6 alkenylene, and substituted and unsubstituted heteroC 2 - 6 alkynylene;
  • Gi is NR Gla and G 2 is ⁇ ( ⁇ ° 2 ⁇ )- ⁇ ⁇ ⁇ , O-L 1 - ⁇ , or CCR ⁇ -L ⁇ R 11 ; or Gi is CHR Gla and G 2 is NCR ⁇ -L ⁇ R 11 or O-I ⁇ -R 11 ;
  • each instance of R Gla and R G2a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or R Gla and one instance of R G2a are joined to form the group -C(R B ) 2 -C(R B ) 2 -;
  • L 1 is a linker selected from the group consisting of substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenylene, substituted and unsubstituted heteroalkynylene, substituted and unsubstituted
  • heterocyclylene substituted and unsubstituted carbocyclylene, substituted and unsubstituted arylene, substituted and unsubstituted heteroarylene, and combinations thereof;
  • R is a hydrophobic group selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroarylalkyl, substituted and unsubstituted carbocycylalkyl, and substituted and unsubstituted heterocyclylalkyl;
  • each instance of R D1 , R D2 , and R D3 is independently hydrogen or substituted or unsubstituted alkyl
  • R m is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;
  • G 5 is O, S, or NR E ;
  • each instance of R E and R G is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group
  • each instance of R Jl and R J 2 is independently hydrogen, halogen, or substituted or unsubstituted alkyl
  • each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
  • a and k are each independently 0, 1, or 2, provided when k is 0 then R A is absent, and when a is 0 then R is absent;
  • each instance of R X and R z is independently hydrogen, halogen, substituted or unsubstituted alkyl, cyclopropyl, -CN, -OR XI , or -NHR XI , wherein R XI is hydrogen, substituted or unsubstituted alkyl, an oxygen protecting group when attached to an oxygen, or a nitrogen protecting group when attached to a nitrogen, or R X A and IT z are joined to form a substituted or unsubstituted 5-membered heterocyclic ring;
  • R X A and E are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring.
  • kinase inhibitors e.g. , JAK inhibitors, e.g., JAK3 inhibitors
  • the compounds may covalently or non-covalently bind to the kinase.
  • the compounds including a hydrophobic moiety R may signal to the intracellular protein homeostasis machinery to induce degradation of the targeted kinase.
  • pharmaceutical compositions and kits comprising such compounds, and methods of their use and treatment, e.g., for reducing the activity of a kinase, and/or treating and/or preventing a condition associated with aberrant activity of a kinase (e.g. , a kinase)
  • proliferative disease inflammatory disorder, autoimmune disorder, painful condition, or viral infection
  • inflammatory disorder autoimmune disorder, painful condition, or viral infection
  • Wi is N
  • W 2 is N and W 3 is CR X
  • Wi is N
  • W 2 is CH
  • W 3 is N.
  • G 5 is O, S, or NR E ;
  • each instance of R is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group
  • each instance of R X and R z is independently hydrogen, halogen, substituted or unsubstituted alkyl, cyclopropyl, -CN, -OR XI , or -NHR XI , wherein R XI is hydrogen, substituted or unsubstituted alkyl, an oxygen protecting group when attached to an oxygen, or a nitrogen protecting group when attached to a nitrogen, or R X A and R z" are joined to form a substituted or unsubstituted 5-membered heterocyclic ring; or R X A and E are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring.
  • R z is hydrogen or -NHR X1 (e.g., -NH 2 ).
  • R z is hydrogen to provide a ring system of formula:
  • R x and R z are joined to form a substituted or unsubstituted 5-membered heterocyclic ring.
  • R x and R z are joined to form a substituted or unsubstituted 5-membered heterocyclic ring.
  • RR XX A aanndd RR zz" aarree jjooiinneedd ttoo ffoorrmm aa substituted or unsubstituted 5-membered heterocyclic ring, provided is a group of formula:
  • R ⁇ is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.
  • R x and R E are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring.
  • R X and R E are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring, provided is a group of formula:
  • R is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group when attached to a nitrogen atom.
  • R x is not joined to form a ring with either R z or R E .
  • R is hydrogen, halogen, substituted or unsubstituted alkyl, cyclopropyl, -CN, -OR XI , or -NHR XI , wherein R XI is hydrogen, substituted or unsubstituted alkyl, an oxygen protecting group when attached to an oxygen, or a nitrogen protecting group when attached to a nitrogen.
  • R is hydrogen.
  • both R X and R z are hydrogen, e.g., to provide a ring system of formula:
  • R x is halogen.
  • R is F.
  • R X is CI.
  • R X is Br.
  • R is I (iodine).
  • R X is halogen ("Hal") and R z is hydro en, e.g., to provide a ring system of formula:
  • R is cyclopropyl. In certain embodiments of Formula (I) or Formula (II), R is substituted alkyl. In certain embodiments of Formula (I) or Formula (II), R is unsubstituted alkyl. In certain embodiments of Formula (I) or Formula (II), R is cyclopropyl. In certain embodiments of Formula (I) or Formula (II), R is substituted alkyl. In certain embodiments of Formula (I) or Formula (II), R is unsubstituted alkyl. In certain embodiments of Formula (I) or Formula (II), R is cyclopropyl. In certain embodiments of Formula (I) or Formula (II), R is substituted alkyl. In certain embodiments of Formula (I) or Formula (II), R is unsubstituted alkyl. In certain embodiments of Formula (I) or Formula (II), R is cyclopropyl. In certain embodiments of Formula (I) or Formula (II), R is substituted alkyl.
  • R is unsubstituted C 1-6 alkyl. In certain embodiments of Formula (I) or Formula (II), R is substituted C 1-6 alkyl. In certain embodiments of Formula (I) or Formula (II), R is unsubstituted C 1-6 alkyl. In certain embodiments of Formula (I) or Formula (II), R is substituted C 1-6 alkyl. In certain embodiments of Formula (I) or Formula
  • R is Ci_6 alkyl substituted with at least one halogen.
  • R X is -CH 3 . In certain embodiments of Formula (I) or Formula (II), R X is substituted methyl. In certain embodiments of Formula (I) or Formula (II), R is -CH 2 F. In certain embodiments of Formula (I) or Formula (II), R is -CHF 2 . In certain embodiments of Formula (I) or Formula (II), R is -CF . In certain embodiments of Formula (I) or Formula
  • R is substituted or unsubstituted ethyl. In certain embodiments of Formula (I) or Formula (II), R is substituted or unsubstituted propyl. In certain embodiments of Formula (I) or Formula (II), R is substituted or unsubstituted butyl. In certain embodiments of Formula (I) or Formula (II), R is substituted or unsubstituted pentyl. In certain embodiments of Formula (I) or Formula (II), R is substituted or unsubstituted ethyl. In certain embodiments of Formula (I) or Formula (II), R is substituted or unsubstituted propyl. In certain embodiments of Formula (I) or Formula (II), R is substituted or unsubstituted butyl. In certain embodiments of Formula (I) or Formula (II), R is substituted or unsubstituted pentyl. In certain
  • R is substituted or unsubstituted hexyl.
  • R X is alkyl or cyclopropyl ("Alk”) and R z is hydrogen, e.g., to provide a ring system of formula:
  • R is -CN.
  • R is -CN and R is h drogen, e.g., to provide a ring system of formula:
  • R x is -OR xl .
  • R is -OR and R is h drogen, e.g., to provide a ring system of formula:
  • R x is -OR xl wherein R xl is hydrogen (i.e., to provide -OH).
  • R x is -OR xl , wherein R xl is
  • R is unsubstituted
  • R is unsubstituted C 1-6 alkyl.
  • R is substituted C 1-6 alkyl.
  • R is C 1-6 alkyl substituted with at least
  • R is -CH 3 .
  • R is substituted methyl.
  • R is -CH 2 F.
  • R is -CHF 2 . In certain embodiments of Formula (I) or Formula (II), R is -CHF 2 .
  • R is -CF 3 .
  • R is substituted or unsubstituted ethyl.
  • Formula (I) or Formula (II)
  • R is substituted or unsubstituted propyl.
  • R is substituted or unsubstituted butyl. In certain embodiments of Formula (I) or
  • R is substituted or unsubstituted pentyl.
  • R is substituted or unsubstituted hexyl.
  • R x is -OR xl , wherein R xl is
  • R is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, ⁇ -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.
  • R x is -NHR X1 .
  • Formula (II) comprises a group of formula:
  • t is 2, 3, 4, 5, or 6.
  • Wi is N
  • W 2 is N
  • W 3 is CR
  • G 5 is NR
  • R is h drogen.
  • Wi is N
  • W 2 is N
  • W 3 is CR .
  • G 5 is NR .
  • R is hydrogen.
  • Wi is N
  • W 2 is N
  • G 3 is CR .
  • G 5 is NR .
  • In certain embod is hydrogen.
  • W is N
  • W 2 is N
  • WW 33 iiss CCRR .
  • G5 is NR .
  • R is hydrogen.
  • t is 4.
  • k is 0 and R A is absent.
  • k is 1. In certain embodiments of Formula (I), k is 1 and R A is a group as described herein attached ortho to the point of attachment to -N(R G )-. In certain embodiments of Formula (I), k is 1 and R A is a group as described herein attached meta to the point of attachment to -N(R G )-.
  • k is 2. In certain embodiments of Formula (I), k is 2, and each R A is independently a group as described herein, wherein one R A is attached ortho and one R A is attached meta to the point of attachment to -N(R G )-. In certain embodiments of Formula (I), k is 2, and each R A is independently a group as described herein, both R A groups are attached ortho to the point of attachment to -N(R G )-. In certain embodiments of Formula (I), k is 2, and each R A is independently a group as described herein, both R A groups are attached meta to the point of attachment to -N(R G )-.
  • k is 1 or 2 and at least one instance of R A is halogen. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is F. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is CI. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is Br. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is I (iodine).
  • k is 2 and both instances of R A are independently halogen. In certain embodiments of Formula (I) or (II), k is 2 and both instances of R A are F. In certain embodiments of Formula (I) or (II), k is 2 and both instances of R A are CI.
  • k is 1 or 2 and at least one instance of R A is substituted alkyl. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R is unsubstituted alkyl. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is unsubstituted Ci_ 6 alkyl. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is substituted Ci- 6 alkyl.
  • k is 1 or 2 and at least one instance of R A is C 1-6 alkyl substituted with at least one halogen. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is -CH 3 . In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is substituted methyl. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is -CH 2 F. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is - CHF 2 .
  • k is 1 or 2 and at least one instance of R A is -CF 3 . In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is substituted or unsubstituted ethyl. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is substituted or unsubstituted propyl. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is substituted or unsubstituted butyl.
  • k is 1 or 2 and at least one instance of R A is substituted or unsubstituted pentyl. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is substituted or unsubstituted hexyl.
  • k is 1 or 2 and at least one instance of R A is substituted or unsubstituted alkenyl, e.g., substituted or unsubstituted C 2 _ 6 alkenyl, substituted or unsubstituted C 2 _ 5 alkenyl, substituted or unsubstituted C 2 - 4 alkenyl, or substituted or unsubstituted C 2 _ 3 alkenyl.
  • k is 1 or 2 and at least one instance of R A is unsubstituted alkenyl.
  • k is 1 or 2 and at least one instance of R A is substituted alkynyl, e.g., substituted or unsubstituted C 2 _ 6 alkynyl, substituted or unsubstituted C 2 _ 5 alkynyl, substituted or unsubstituted C 2 ⁇ alkynyl, or substituted or unsubstituted C 2 _ 3 alkynyl.
  • R A is substituted alkynyl, e.g., substituted or unsubstituted C 2 _ 6 alkynyl, substituted or unsubstituted C 2 _ 5 alkynyl, substituted or unsubstituted C 2 ⁇ alkynyl, or substituted or unsubstituted C 2 _ 3 alkynyl.
  • k is 1 or 2 and at least one instance of R A is unsubstituted alkynyl.
  • k is 1 or 2 and at least one instance of R A is -OR A1 , wherein R A1 is hydrogen (i.e., to provide -OH), or a non-hydrogen group.
  • k is 1 or 2 and at least one instance of R A is -SR A1 , wherein R A1 is hydrogen (i.e., to provide -SH), or a non-hydrogen group.
  • k is 1 or 2 and at least one instance of R is— N(R ) 2 , wherein at least one R is hydrogen (e.g., to provide -NH 2 or NHR A1 ), each R A1 is a non-hydrogen group, or wherein two R A1 groups are joined to form a substituted or unsubstitued heterocyclic or heteroaryl ring.
  • k is 1 or 2 and at least one instance of R A is -CN. In certain embodiments of Formula (I) or (II), k is 1 or 2 and at least one instance of R A is -N0 2 .
  • each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
  • R A comprising a group R A1
  • at least one instance of R A1 is hydrogen.
  • R comprising a group R A1
  • at least one instance of R A1 is substituted or unsubstituted alkyl, e.g. , substituted or
  • Ci_ 6 alkyl e.g., substituted or unsubstituted Cialkyl, substituted or unsubstituted C 2 alkyl, substituted or unsubstituted C 3 alkyl, substituted or unsubstituted C 4 alkyl, substituted or unsubstituted C 5 alkyl, or substituted or unsubstituted Cealkyl.
  • R A1 is substituted or unsubstituted C 2 _ 6 alkenyl, e.g., substituted or unsubstituted C 2 alkenyl, substituted or unsubstituted C 3 alkenyl, substituted or unsubstituted C 4 alkenyl, substituted or unsubstituted C 5 alkenyl, or substituted or unsubstituted Cealkenyl.
  • R A1 is substituted or unsubstituted C 2 _ 6 alkynyl, e.g., substituted or unsubstituted C 2 alkynyl, substituted or unsubstituted C 3 alkynyl, substituted or unsubstituted C 4 alkynyl, substituted or unsubstituted C 5 alkynyl, or substituted or unsubstituted C 6 alkynyl.
  • R A1 is substituted or unsubstituted carbocyclyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R A1 is saturated carbocyclyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R A1 is unsaturated carbocyclyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R A1 is monocyclic C 3 _ 7 carbocyclyl.
  • R A1 is substituted or unsubstituted heterocyclyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R A1 is saturated heterocyclyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R A1 is unsaturated heterocyclyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R A1 is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are
  • R A1 is 3- to 7- membered, monocyclic heterocyclyl.
  • R A1 is substituted or unsubstituted aryl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R A1 is C 6 -io aryl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R A1 is monocyclic aryl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R A1 is substituted phenyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R A1 is unsubstituted phenyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R A1 is bicyclic aryl.
  • R A1 is substituted or unsubstituted heteroaryl.
  • at least one instance of R A1 is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • at least one instance of R A1 is monocyclic heteroaryl.
  • at least one instance of R A1 is 5- or 6-membered, monocyclic heteroaryl.
  • at least one instance of R A1 is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits.
  • R A1 is a nitrogen protecting group when attached to a nitrogen atom.
  • at least one instance of R A1 is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to a nitrogen atom.
  • R A1 is an oxygen protecting group when attached to an oxygen atom.
  • R A1 is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, ⁇ -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom.
  • R A1 is a sulfur protecting group when attached to a sulfur atom.
  • R A1 is acetamidomethyl, ⁇ -Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.
  • two instances of R A1 are joined to form an unsaturated heterocyclic ring.
  • two instances of R A1 are joined to form a heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • two instances of R A1 are joined to form a 3- to 7-membered, monocyclic heterocyclic ring.
  • two instances of R A1 are joined to form a substituted or unsubstituted, 5- to 6- membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • two instances of R A1 are joined to form a substituted or unsubstituted, 9- to 10-membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • each instance of R is independently hydrogen, halogen, substituted or unsubstituted Ci_6 alkyl, or -OR A1 , wherein R A1 is substituted or unsubstituted C 1-6 alkyl.
  • each instance of R A is independently hydrogen, halogen, unsubstituted C 1-6 alkyl, C 1-6 alkyl substituted with at least one halogen, or -OR A1 , wherein R A1 is unsubstituted C 1-6 alkyl.
  • k is 1; and the group:
  • k is 2 and the group:
  • At least one instance of R is -OR , and and the roup:
  • At least one instance of R is halogen, and and the group:
  • R Y1 which is attached to a compound of
  • Formula (I) is a group of formula:
  • G 1; G 2 , L 1 , L 3 , R H , and R B are as defined herein.
  • R Y2 attached to a compound of
  • Formula (II) is a group of formula:
  • G 1; G 2 , L 1 , L 3 , R H , and R B are as defined herein.
  • each instance of R B provided in Formula (I) or
  • R is hydrogen. In certain embodiments of Formula (I) or Formula (II), at least two instances of R are hydrogen. In certain embodiments of Formula (I) or Formula (II), at least three instances of R are hydrogen. In certain embodiments of Formula (I) or Formula (II), at least four instances of R are hydrogen. In certain embodiments of Formula (I) or Formula (II), at least five instances of R are hydrogen. In certain embodiments of Formula (I) or Formula (II), at least six instances of R are hydrogen. In certain embodiments of Formula (I) or Formula (II), at least seven instances of R are hydrogen. In certain embodiments of Formula (I) or Formula (II), all instances of R are hydrogen.
  • R is halogen.
  • R is F. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is CI. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is Br. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is I (iodine). In certain embodiments of Formula (I) or Formula (II), at least two instances of R are independently halogen. In certain embodiments of Formula (I) or Formula (II), at least two instances of R are F. In certain embodiments of Formula (I) or Formula (II), at least two instances of R are CI.
  • R is substituted alkyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is unsubstituted alkyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is unsubstituted Ci_6 alkyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is substituted Ci_6 alkyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is C - alkyl substituted with at least one halogen. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is -CH 3 .
  • At least one instance of R is substituted methyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is -CH 2 F. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is -CHF 2 . In certain embodiments of Formula (I) or Formula (II), at least one instance of R is -CF 3 . In certain embodiments of Formula (I) or Formula (II), at least one instance of R is substituted or unsubstituted ethyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is substituted or unsubstituted propyl.
  • At least one instance of R is substituted or unsubstituted butyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is substituted or unsubstituted pentyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is substituted or unsubstituted hexyl.
  • R is substituted alkenyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is unsubstituted alkenyl.
  • R is substituted alkynyl. In certain embodiments of Formula (I) or Formula (II), at least one instance of R is unsubstituted alkynyl.
  • At least one instance of R B is -
  • R A1 is hydrogen (i.e., to provide -OH), or a non-hydrogen group.
  • At least one instance of R B is -
  • R A1 is hydrogen (i.e., to provide -SH), or a non-hydrogen group.
  • At least one instance of R B is—
  • R A1 is hydrogen (e.g., to provide -NH 2 or NHR A1 ), each R A1 is a non-hydrogen group, or wherein two R A1 groups are joined to form a substituted or unsubstitued heterocyclic or heteroaryl ring.
  • At least one instance of R B is -
  • At least one instance of R B is -
  • At least one instance of R B is -
  • At least one instance of R B is -
  • At least one instance of R B is -
  • At least one instance of R B is -
  • At least one instance of R B is -
  • At least one instance of R B is -
  • At least one instance of R B is -
  • At least one instance of R B is -
  • At least one instance of R B is -
  • At least one instance of R B is -
  • At least one instance of R B is -
  • each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
  • R B comprising a group R A1
  • at least one instance of R A1 is hydrogen.
  • R comprising a group R A1
  • at least one instance of R A1 is substituted or unsubstituted alkyl, e.g., substituted or
  • unsubstitutedCi-6 alkyl e.g., substituted or unsubstituted Cialkyl, substituted or unsubstituted C 2 alkyl, substituted or unsubstituted C 3 alkyl, substituted or unsubstituted C 4 alkyl, substituted or unsubstituted C 5 alkyl, or substituted or unsubstituted Cealkyl.
  • R A1 is substituted or unsubstituted C 2 _ 6 alkenyl, e.g., substituted or unsubstituted C 2 alkenyl, substituted or unsubstituted C 3 alkenyl, substituted or unsubstituted C 4 alkenyl, substituted or unsubstituted C 5 alkenyl, or substituted or unsubstituted C 6 alkenyl
  • R A1 is substituted or unsubstituted C 2 _ 6 alkynyl, e.g., substituted or unsubstituted C 2 alkynyl, substituted or unsubstituted C 3 alkynyl, substituted or unsubstituted C 4 alkynyl, substituted or unsubstituted C 5 alky
  • two instances of R A1 are joined to form an unsaturated heterocyclic ring.
  • two instances of R A1 are joined to form a heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • two instances of R A1 are joined to form a 3- to 7-membered, monocyclic heterocyclic ring.
  • two instances of R A1 are joined to form a substituted or unsubstituted, 5- to 6- membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • two instances of R A1 are joined to form a substituted or unsubstituted, 9- to 10-membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • each instance of R B is independently hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, or -OR A1 , wherein R A1 is substituted or unsubstituted C 1-6 alkyl.
  • each instance of R is independently hydrogen, halogen, unsubstituted C 1-6 alkyl, C 1-6 alkyl substituted with at least one halogen, or -OR A1 , wherein R A1 is unsubstituted Ci_6 alkyl.
  • L 3 is a bond or a linker selected from the group consisting of substituted and unsubstituted Ci-ealkylene, substituted and unsubstituted C 2 - 6 alkenylene, substituted and unsubstituted C 2 - 6 alkynylene, substituted and unsubstituted heteroCi-ealkylene, substituted and unsubstituted heteroC 2 - 6 alkenylene, and substituted and unsubstituted heteroC 2 - 6 alkynylene.
  • L 3 is a bond, i.e., a direct, covalent single bond.
  • L 3 is a substituted or unsubstituted Ci ⁇ alkylene, e.g., substituted or unsubstituted C 2 - 6 alkylene, substituted or unsubstituted C 3 _ 6 alkylene, substituted or unsubstituted C ⁇ alkylene, substituted or unsubstituted C 5 _ 6 alkylene, substituted or unsubstituted C 2 - 5 alkylene, substituted or unsubstituted C 2 - alkylene, substituted or unsubstituted C 2 - 3 alkylene, substituted or unsubstituted Qalkylene, substituted or unsubstituted C 2 alkylene, substituted or unsubstituted C 3 alkylene, substituted or unsubstituted C 4 alkylene, substituted or unsubstituted C 5 alkylene, or substituted or unsubstituted C 6 alky
  • L 3 is a substituted or unsubstituted C 2 - 6 alkenylene, e.g., substituted or unsubstituted C 3 _ 6 alkenylene, substituted or unsubstituted C ⁇ alkenylene, substituted or unsubstituted C 5 _ 6 alkenylene, substituted or unsubstituted C 2 - 5 alkenylene, substituted or unsubstituted C 2 - alkenylene, substituted or unsubstituted C 2 - 3 alkenylene, substituted or unsubstituted C 2 alkenylene, substituted or unsubstituted C 3 alkenylene, substituted or unsubstituted C 4 alkenylene, substituted or unsubstituted Csalkenylene, or substituted or unsubstituted Cealkenylene.
  • L 3 is a substituted or unsubstituted C 2 - 6 alkenylene, e.g., substituted
  • L 3 is a substituted or unsubstituted C 2 - 6 alkynylene, e.g., substituted or unsubstituted C 3 _ 6 alkynylene, substituted or unsubstituted C ⁇ alkynylene, substituted or unsubstituted C 5 _ 6 alkynylene, substituted or unsubstituted C 2 - 5 alkynylene, substituted or unsubstituted C 2 -4alkynylene, substituted or unsubstituted C 2 - 3 alkynylene, substituted or unsubstituted C 2 alkynylene, substituted or unsubstituted C 3 alkynylene, substituted or unsubstituted C 4 alkynylene, substituted or unsubstituted C 5 alkynylene, or substituted or unsubstituted C 6 alkynylene.
  • C 3 _ 6 alkynylene substituted or unsubstituted
  • L 3 is a substituted or unsubstituted heteroCi-ealkylene, e.g., substituted or unsubstituted heteroC 2 - 6 alkylene, substituted or unsubstituted heteroC 3 _ 6 alkylene, substituted or unsubstituted heteroC 4 _ 6 alkylene, substituted or unsubstituted heteroCs ⁇ alkylene, substituted or unsubstituted heteroC 2 - 5 alkylene, substituted or unsubstituted heteroC 2 - alkylene, substituted or unsubstituted heteroC 2 - 3 alkylene, substituted or unsubstituted heteroCialkylene, substituted or unsubstituted heteroCialkylene, substituted or unsubstituted heteroCsalkylene, substituted or unsubstituted heteroC 4 alkylene, substituted or unsubstituted heteroCsalkylene, substituted or unsubstituted heteroCsalkylene
  • L is unsubstituted heteroCi-ealkylene.
  • the heteroC 2 - 6 alkylene comprises includes one, two, or three heteroatoms in the heteroalkylene chain, wherein the heteroatoms are independently nitrogen, oxygen, or sulfur.
  • L 3 is a substituted or unsubstituted heteroC 2 - 6 alkenylene, e.g., substituted or unsubstituted heteroC 3 _ 6 alkenylene, substituted or unsubstituted heteroC ⁇ alkenylene, substituted or unsubstituted heteroCs_ 6 alkenylene, substituted or unsubstituted heteroC 2 - 5 alkenylene, substituted or unsubstituted heteroC 2 ⁇ alkenylene, substituted or unsubstituted heteroC 2 - 3 alkenylene, substituted or unsubstituted heteroC 2 alkenylene, substituted or unsubstituted heteroCsalkenylene, substituted or unsubstituted heteroC 4 alkenylene, substituted or unsubstituted
  • heteroCsalkenylene or substituted or unsubstituted heteroCealkenylene.
  • L is unsubstituted heteroC 2 - 6 alkenylene.
  • the heteroC 2 - 6 alkenylene comprises one, two, or three heteroatoms in the heteroalkenylene chain, wherein the heteroatoms are independently nitrogen, oxygen, or sulfur.
  • L 3 is a substituted or unsubstituted heteroC 2 - 6 alkynylene, e.g., substituted or unsubstituted heteroC 2 - 6 alkynylene, substituted or unsubstituted heteroC 3 _ 6 alkynylene, substituted or unsubstituted heteroC 4 _ 6 alkynylene, substituted or unsubstituted heteroCs ⁇ alkynylene, substituted or unsubstituted heteroC 2 - 5 alkynylene, substituted or unsubstituted heteroC 2 ⁇ alkynylene, substituted or unsubstituted heteroC 2 - 3 alkynylene, substituted or unsubstituted heteroC 2 alkynylene, substituted or unsubstituted heteroC 3 alkynylene, substituted or unsubstituted
  • L is unsubstituted heteroalkynylene.
  • L 3 is a substituted or unsubstituted heteroC 2 - 6 alkynylene
  • L 3 includes one, two, or three heteroatoms in the heteroalkynylene chain, wherein the heteroatoms are independently nitrogen, oxygen, or sulfur.
  • Gi is NR Gla and G 2 is ⁇ ( ⁇ ° 2 ⁇ )- ⁇ ⁇ ⁇ , O-L 1 - ⁇ , or CCR ⁇ -L ⁇ R 11 ; or Gi is CHR Gla and G 2 is ⁇ ( ⁇ ° 2 ⁇ )- ⁇ ⁇ ⁇ or O-I ⁇ -R 11 ; and each instance of R Gla and R G2a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or R Gla and one instance of R G2a are joined to form the group - C(R B ) 2 -C(R B ) 2 -.
  • Gi is NR Gla . In certain embodiments of Formula (I) or Formula (II), Gi is CHR Gla .
  • G 2 is NCR ⁇ -L ⁇ R 11 .
  • G 2 is O-L -R .
  • R Gla is hydrogen
  • R Gla is substituted or unsubstituted alkyl.
  • R Gla is substituted alkyl.
  • R Gla is unsubstituted alkyl.
  • R Gla is unsubstituted C 1-6 alkyl.
  • R Gla is substituted Ci_ 6 alkyl.
  • R Gla is Ci_6 alkyl substituted with at least one halogen.
  • R Gla is -CH 3 . In certain embodiments of Formula (I) or Formula (II), R Gla is substituted methyl. In certain embodiments of Formula (I) or Formula (II), R Gla is -CH 2 F. In certain embodiments of Formula (I) or Formula (II), R Gla is -CHF 2 . In certain embodiments of Formula (I) or Formula (II), R Gla is -CF 3 . In certain embodiments of Formula (I) or Formula (II), R Gla is substituted or unsubstituted ethyl. In certain embodiments of Formula (I) or Formula (II), R Gla is substituted or unsubstituted propyl.
  • R Gla is substituted or unsubstituted butyl. In certain embodiments of Formula (I) or Formula (II), R Gla is substituted or unsubstituted pentyl. In certain embodiments of Formula (I) or Formula (II), R Gla is substituted or unsubstituted pentyl. In certain embodiments of Formula (I) or Formula (II), R Gla is substituted or unsubstituted pentyl.
  • R Gla is substituted or unsubstituted hexyl.
  • R Gla is a nitrogen protecting group.
  • Gi is NR Gla
  • R Gla is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
  • R G2a is hydrogen
  • R G2a is substituted or unsubstituted alkyl. In certain embodiments of Formula (I) or Formula (II), R G2a is substituted alkyl. In certain embodiments of Formula (I) or Formula (II), R G2a is unsubstituted alkyl. In certain embodiments of Formula (I) or Formula (II), R G2a is unsubstituted Ci_6 alkyl. In certain embodiments of Formula (I) or Formula (II), R G2a is substituted Ci_6 alkyl. In certain embodiments of Formula (I) or Formula (II), R G2a is Ci_6 alkyl substituted with at least one halogen.
  • R G2a is -CH 3 . In certain embodiments of Formula (I) or Formula (II), R G2a is substituted methyl. In certain embodiments of Formula (I) or Formula (II), R G2a is -CH 2 F. In certain embodiments of Formula (I) or Formula (II), R G2a is -CHF 2 . In certain embodiments of Formula (I) or Formula (II), R G2a is -CF 3 . In certain embodiments of Formula (I) or Formula (II), R G2a is substituted or unsubstituted ethyl. In certain embodiments of Formula (I) or Formula (II), R G2a is substituted or unsubstituted propyl. In certain embodiments of Formula (I) or Formula (II), R G2a is -CH 3 . In certain embodiments of Formula (I) or Formula (II), R G2a is substituted methyl. In certain embodiments of Formula (I) or Formula (II), R G2a is
  • R G2a is substituted or unsubstituted butyl. In certain embodiments of Formula (I) or Formula (II), R G2a is substituted or unsubstituted pentyl. In certain embodiments of Formula (I) or Formula (II), R G2a is substituted or unsubstituted pentyl. In certain embodiments of Formula (I) or Formula (II), R G2a is substituted or unsubstituted pentyl. In certain embodiments of Formula (I) or Formula (II), R G2a is substituted or unsubstituted pentyl. In certain embodiments of Formula (I) or Formula (II), R G2a is substituted or unsubstituted pentyl. In certain embodiments of Formula (I) or Formula (II), R G2a is substituted or unsubstituted pentyl. In certain embodiments of Formula (I) or Formula (II), R G2a is substituted or unsubstituted penty
  • R G2a is substituted or unsubstituted hexyl.
  • R G2a is a nitrogen protecting group.
  • triphenylmethyl acetyl, or Ts.
  • L 1 , R H , and R B are as defined herein.
  • each instance of R B is hydrogen.
  • R Gla and R G2a are joined to form the group -C(R B ) 2 -C(R B ) 2 - i.e., to provide a group of the formula:
  • R G2a and R B are as defined herein.
  • each instance of R B is hydrogen.
  • R G2a is substituted or unsubstituted alkyl, e.g., -CH 3 , or substituted or unsubstituted hydroxyl, e.g., -OH or -OCH .
  • R Y1 is -I ⁇ -R 11 wherein L 1 and R H are as defined herein.
  • R Y2 is -L 1 -R H wherein L 1 and R H are as defined herein.
  • a is 1. In certain embodiments of Formula (I) or (II), a is 1 and R is a group as described herein attached ortho to the point of attachment to 3 ⁇ 4 R J2 . In certain embodiments of Formula (I) or (II), a is 1 and R is a
  • a is 2. In certain embodiments of Formula (I) or (II), a is 2, and each R is independently a group as described herein, wherein one R c is attached ne R c
  • ortho and o is attached meta to the point of attachment to
  • a is 2, and each R L is independently as described herein, both R groups are attached ortho to the point of
  • a is 2, and each R is independently as described herein, both R groups are attached meta to the point of
  • a is 1 or 2 and at least one instance of R is halogen. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is F. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is CI. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is Br. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is I (iodine). In certain embodiments of Formula (I) or (II), a is 2 and both instances of R are independently halogen. In certain embodiments of Formula (I) or (II), a is 2 and both instances of R are F. In certain embodiments of Formula (I) or (II), a is 2 and both instances of R are CI.
  • a is 1 or 2 and at least one instance of R is substituted alkyl. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is unsubstituted alkyl. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is unsubstituted C 1-6 alkyl. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is substituted Ci_6 alkyl.
  • a is 1 or 2 and at least one instance of R is Ci-6 alkyl substituted with at least one halogen. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is -CH 3 . In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is substituted methyl. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is -CH 2 F. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is - CHF 2 .
  • a is 1 or 2 and at least one instance of R is -CF . In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is substituted or unsubstituted ethyl. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is substituted or unsubstituted propyl. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is substituted or unsubstituted butyl.
  • a is 1 or 2 and at least one instance of R is substituted or unsubstituted pentyl. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is substituted or unsubstituted hexyl.
  • a is 1 or 2 and at least one instance of R is substituted or unsubstituted alkenyl, e.g., substituted or unsubstituted C 2 _ 6 alkenyl, substituted or unsubstituted C 2 _salkenyl, substituted or unsubstituted C 2 _ 4 alkenyl, or substituted or unsubstituted C 2 _ 3 alkenyl.
  • a is 1 or 2 and at least one instance of R is substituted or unsubstituted alkynyl, e.g., substituted or unsubstituted C 2 _ 6 alkenyl, substituted or unsubstituted C 2 _salkenyl, substituted or unsubstituted C 2 _ 4 alkenyl, or substituted or unsubstituted C 2 _ 3 alkenyl.
  • a is 1 or 2 and at least one instance of R c is -OR A1 , wherein R A1 is hydrogen (i.e., to provide -OH), or a non-hydrogen group.
  • a is 1 or 2 and at least one instance of R c is -SR A1 , wherein R A1 is hydrogen (i.e., to provide -SH), or a non-hydrogen group.
  • a is 1 or 2 and at least one instance of R c is— N(R A1 ) 2 , wherein at least one R A1 is hydrogen (e.g., to provide -NH 2 or NHR A1 ), each R A1 is a non-hydrogen group, or wherein two R A1 groups are joined to form a substituted or unsubstitued heterocyclic or heteroaryl ring.
  • a is 1 or 2 and at least one instance of R is -CN. In certain embodiments of Formula (I) or (II), a is 1 or 2 and at least one instance of R is -N0 2 .
  • each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
  • R c comprising a group R A1
  • at least one instance of R A1 is hydrogen.
  • R comprising a group R A1
  • at least one instance of R A1 is substituted or unsubstituted alkyl, e.g. , substituted or
  • unsubstitutedCi- 6 alkyl e.g., substituted or unsubstituted Cialkyl, substituted or unsubstituted C 2 alkyl, substituted or unsubstituted C 3 alkyl, substituted or unsubstituted C 4 alkyl, substituted or unsubstituted C 5 alkyl, or substituted or unsubstituted Cealkyl.
  • R A1 is substituted or unsubstituted C 2 _ 6 alkenyl, e.g., substituted or unsubstituted C 2 alkenyl, substituted or unsubstituted C 3 alkenyl, substituted or unsubstituted C 4 alkenyl, substituted or unsubstituted C 5 alkenyl, or substituted or unsubstituted C 6 alkenyl
  • R A1 is substituted or unsubstituted C 2 _ 6 alkynyl, e.g., substituted or unsubstituted C 2 alkynyl, substituted or unsubstituted C 3 alkynyl, substituted or unsubstituted C 4 alkynyl, substituted or unsubstituted C 5 alkynyl, or substituted or unsubstituted Cealkynyl.
  • two instances of R A1 are joined to form an unsaturated heterocyclic ring.
  • two instances of R A1 are joined to form a heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • two instances of R A1 are joined to form a 3- to 7-membered, monocyclic heterocyclic ring.
  • two instances of R A1 are joined to form a substituted or unsubstituted, 5- to 6- membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • two instances of R A1 are joined to form a substituted or unsubstituted, 9- to 10-membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • each instance of R c is independently hydrogen, halogen, substituted or unsubstituted Ci_6 alkyl, or -OR A1 , wherein R A1 is substituted or unsubstituted C 1-6 alkyl.
  • each instance of R is independently hydrogen, halogen, unsubstituted C 1-6 alkyl, C 1-6 alkyl substituted with at least one halogen, or -OR A1 , wherein R A1 is unsubstituted C 1-6 alkyl.
  • G 5 is O, S, or NR E .
  • R E is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.
  • G 5 is O. In certain embodiments of Formula (I) or Formula (II), G 5 is S. In certain embodiments of Formula (I) or Formula (II), G 5 is NR E .
  • R E is hydrogen.
  • R E is substituted or unsubstituted Ci alkyl, e.g., substituted or unsubstituted Ci alkyl, substituted or
  • R is substituted or unsubstituted methyl. In certain embodiments of Formula (I) or Formula (II), R is substituted or unsubstituted ethyl. In certain embodiments of Formula (I) or Formula (II), R is substituted or unsubstituted propyl. In certain embodiments of Formula (I) or Formula (II),
  • R is substituted or unsubstituted butyl.
  • R is a nitrogen protecting group.
  • R is a nitrogen protecting group selected from the group consisting of Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, and Ts.
  • G 5 is NR E and R E is hydrogen or substituted or unsubstituted Ci alkyl (e.g., -CH 3 , -CF 3 ).
  • R G is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.
  • R G is hydrogen.
  • R G is substituted or unsubstituted C 1-6 alkyl, e.g., substituted or unsubstituted C 1-2 alkyl, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted Cis alkyl.
  • R G is substituted or unsubstituted methyl.
  • R G is substituted or unsubstituted ethyl.
  • R G is substituted or unsubstituted propyl. In certain embodiments of Formula (I) or Formula (II), R G is substituted or unsubstituted butyl. In certain embodiments of Formula (I) or Formula (II), R G is a nitrogen protecting group. In certain embodiments of Formula (I) or Formula (II), R G is a nitrogen protecting group selected from the group consisting of Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
  • R G is hydrogen or substituted or unsubstituted C 1-2 alkyl (e.g., -CH 3 , -CF 3 ).
  • each instance of R J1 and R J2 is independently hydrogen, halogen, or substituted or unsubstituted alkyl.
  • R J1 is hydrogen. In certain embodiments of Formula (I) or Formula (II), R is hydrogen. In certain embodiments of Formula (I) or Formula (II), both R Jl and R J 2 are hydrogen. In certain embodiments of
  • R J1 is halogen. In certain embodiments of Formula (I) or Formula (II), R is halogen. In certain embodiments of Formula (I) or Formula (II), R J1 is F. In certain embodiments of Formula (I) or Formula (II), R is F. In certain embodiments of Formula (I) or Formula (II), both R and R are F. In certain embodiments of Formula (I) or Formula (II), R J1 is CI. In certain embodiments of Formula (I) or Formula (II), R is CI. In certain embodiments of Formula (I) or Formula (II), both R J1 and R J2 are CI.
  • R is substituted alkyl. In certain embodiments of Formula (I) or Formula (II), at least one of
  • R Jl and R J2 is unsubstituted alkyl. In certain embodiments of Formula (I) or Formula (II), at least one of R Jl and R J2 is unsubstituted C 1-6 alkyl. In certain embodiments of Formula (I) or
  • R Jl and R J2 are substituted C 1-6 alkyl.
  • Formula (I) or Formula (II) at least one of R Jl and R J2 is Ci_6 alkyl substituted with at least one halogen. In certain embodiments of Formula (I) or Formula (II), at least one of R J1 and
  • R J2 is -CH 3 .
  • R J2 is substituted methyl.
  • at least one of R Jl and R J2 is -CH 2 F.
  • at least one of R Jl and R J2 is -CHF 2 .
  • at least one of R Jl and R J2 is -CF 3 .
  • R Jl and R J2 is substituted or unsubstituted ethyl.
  • R Jl and R J2 is substituted or unsubstituted ethyl.
  • Formula (II), at least one of R Jl and R J2 is substituted or unsubstituted propyl. In certain embodiments of Formula (I) or Formula (II), at least one of R Jl and R J2 is substituted or unsubstituted butyl. In certain embodiments of Formula (I) or Formula (II), at least one of
  • R Jl and R J2 is substituted or unsubstituted pentyl.
  • R Jl and R J2 are substituted or unsubstituted hexyl.
  • R x and R xl are substituted or unsubstituted hexyl.
  • R x is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, or -OR XI , wherein R XI is hydrogen, substituted or unsubstituted alkyl, or an oxygen protecting group.
  • R x is hydrogen
  • R x is halogen. In certain embodiments of Formula (I) or Formula (II), R is F. In certain embodiments of Formula (I) or Formula (II), R is CI. In certain embodiments of Formula (I) or Formula (II),
  • R X is Br. In certain embodiments of Formula (I) or Formula (II), R X is I (iodine).
  • R x is substituted alkyl.
  • R is unsubstituted alkyl. In certain embodiments of Formula (I) or Formula (II), R is unsubstituted C 1-6 alkyl. In certain embodiments of Formula (I) or Formula (II), R is substituted C 1-6 alkyl. In certain embodiments of Formula (I) or Formula (II), R is C 1-6 alkyl substituted with at least one halogen. In certain embodiments of Formula (I) or Formula (II), R is -CH 3 . In certain embodiments of Formula (I) or Formula (II), R is substituted methyl. In certain embodiments of Formula (I) or Formula (II), R is substituted methyl.
  • R is -CH 2 F. In certain embodiments of Formula (I) or Formula (II), R is -CHF 2 . In certain embodiments of Formula (I) or Formula (II), R is -CHF 2 . In certain embodiments of Formula (I) or Formula (II), R is -CH 2 F. In certain embodiments of Formula (I) or Formula (II), R is -CHF 2 . In certain embodiments of Formula (I) or Formula
  • R X is -CF 3 .
  • R X is substituted or unsubstituted ethyl.
  • R is substituted or unsubstituted propyl.
  • R is substituted or unsubstituted butyl.
  • R is substituted or unsubstituted pentyl.
  • R is substituted or unsubstituted hexyl.
  • R x is -CN.
  • R x is -OR xl , wherein
  • R XI is hydrogen (i.e., to provide -OH).
  • R x is -OR xl , wherein
  • R XI is substituted alkyl. In certain embodiments of Formula (I) or Formula (II), R XI is unsubstituted alkyl. In certain embodiments of Formula (I) or Formula (II), R XI is
  • R XI is substituted Ci certain embodiments of Formula (I) or Formula (II), R XI
  • R XI is -CH 3 . In certain embodiments of Formula (I) or Formula (II), R XI is substituted methyl. In certain embodiments of Formula (I) or Formula (II), R XI is -CH 2 F. In certain embodiments of Formula (I) or Formula (II), R XI is -CHF 2 . In certain embodiments of
  • R XI is -CF .
  • R is substituted or unsubstituted ethyl. In certain embodiments of Formula (I) or
  • R XI is substituted or unsubstituted propyl.
  • R XI is substituted or unsubstituted butyl.
  • R XI is substituted or unsubstituted pentyl.
  • R XI is substituted or unsubstituted hexyl.
  • R x is -OR xl , wherein
  • R XI is an oxygen protecting group.
  • R xl is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, ⁇ -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.
  • each instance of R D1 , R D2 , and R D3 is independently hydrogen or substituted or unsubstituted alkyl
  • R m is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group, and represents a single bond or a double bond.
  • the group of formula s a tached meta or para to the point of certain embodiments, the group is attached meta to the point of attachment. In certain embodiments, the group is attached para to the point of attachment.
  • R D3 is hydrogen.
  • each of R D2 and R D3 is hydrogen, and R D1 is -CH 3 .
  • each of R D1 and R D2 is hydrogen, and R D3 is -CH 2 N(R Dla ) 2 .
  • each of R D1 and R D2 is hydrogen, and R D3 is -CH 2 0R Dla .
  • each of R D1 and R D2 is hydrogen, R D3 is - CH 2 N(R Dla ) 2 , and R Dla is hydrogen.
  • each of R m and R u/ is hydrogen, R UJ is -CH 2 N(R ma ) 2 , and R ma is methyl.
  • each of R D1 and R D2 is hydrogen, R D3 is - CH 2 OR Dla , and R Dla is hydrogen.
  • each of R D1 and R D2 is hydrogen, R D3 is -CH 2 OR Dla , and R Dla is methyl.
  • R m is hydrogen. In certain embodiments of Formula (I) or Formula (II), R m is substituted or unsubstituted alkyl. In certain embodiments of Formula (I) or Formula (II), R m is a nitrogen protecting group.
  • R Y1 is -I ⁇ -R 11 , wherein L 1 and R H are as defined herein, or R Yl is a group of formula:
  • L 3 , Gi, and R B is as defined herein, and G 2 is N(R G2a )-L 1 -R H , O-I ⁇ -R 11 , or C(R G2a )-
  • R Y2 is -I ⁇ -R 11 , wherein
  • L 1 and R H n are as defined herein, or R Y2 is a roup of formula:
  • L 3 , Gi, and R B is as defined herein, and G 2 is N(R G2a )-L 1 -R H , O-I ⁇ -R 11 , or C(R G2a )-
  • L 1 is a linker selected from the group consisting of the following divalent moieties: substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenylene, substituted and unsubstituted heteroalkynylene, substituted and unsubstituted heterocyclylene, substituted and unsubstituted carbocyclylene, substituted and unsubstituted arylene, substituted and unsubstituted heteroarylene, and combinations thereof.
  • L 1 being a combination of at least two instances of the divalent moieties described herein refers to a linker consisting of at least one instance of a first divalent moiety and at least one instance of a second divalent moiety, wherein the first and second divalent moieties are the same or different and are within the scope of the divalent moieties described herein, and the instances of the first and second divalent moieties are consecutive covalently attached to each other.
  • L 1 is a combination of alkylene and heteroalkylene
  • linkers -alkylene- heteroalkylene-, -alkylene- (heteroalkylene) 2 -, and -heteroalkylene-alkylene-heteroalkylene- are all within the scope of L 1 , wherein each instance of alkylene in any one of the linkers may be the same or different, and each instance of heteroalkylene in any one of the linkers may be the same or different.
  • L 1 comprises at least one instance of substituted or unsubstituted alkylene, e.g., substituted or unsubstituted C ⁇ alkylene, substituted or unsubstituted Ci ⁇ alkylene, substituted or unsubstituted C 2 _ 3 alkylene, substituted or unsubstituted C 3 ⁇ alkylene, substituted or unsubstituted C ⁇ salkylene, substituted or unsubstituted C 5 _ 6 alkylene, substituted or unsubstituted C 3 _ 6 alkylene, or substituted or unsubstituted C ⁇ alkylene.
  • substituted or unsubstituted alkylene e.g., substituted or unsubstituted C ⁇ alkylene, substituted or unsubstituted Ci ⁇ alkylene, substituted or unsubstituted C 2 _ 3 alkylene, substituted or unsubstituted C 3 ⁇ alkylene, substituted or unsubstit
  • Exemplary alkylene groups include unsubstituted alkylene groups such as methylene (-CH 2 -), ethylene (-(CH 2 ) 2 -), ⁇ -propylene (-(CH 2 ) 3 -), w-butylene (- (CH 2 ) 4 -), w-pentylene (-(CH 2 )s-), and w-hexylene (-(CH 2 )6-).
  • L 1 comprises at least one instance of substituted or unsubstituted alkenylene, e.g., substituted or unsubstituted C 2 _ 6 alkenylene, substituted or unsubstituted C 2 _ 3 alkenylene, substituted or unsubstituted C 3 ⁇ alkenylene, substituted or unsubstituted C ⁇ salkenylene, or substituted or unsubstituted Cs ⁇ alkenylene.
  • substituted or unsubstituted alkenylene e.g., substituted or unsubstituted C 2 _ 6 alkenylene, substituted or unsubstituted C 2 _ 3 alkenylene, substituted or unsubstituted C 3 ⁇ alkenylene, substituted or unsubstituted C ⁇ salkenylene, or substituted or unsubstituted Cs ⁇ alkenylene.
  • L 1 comprises at least one instance of substituted or unsubstituted alkynylene, e.g., substituted or unsubstituted C 2 _ 6 alkynylene, substituted or unsubstituted C 2 _ 3 alkynylene, substituted or unsubstituted C 3 ⁇ alkynylene, substituted or unsubstituted C ⁇ salkynylene, or substituted or unsubstituted Cs ⁇ alkynylene.
  • substituted or unsubstituted alkynylene e.g., substituted or unsubstituted C 2 _ 6 alkynylene, substituted or unsubstituted C 2 _ 3 alkynylene, substituted or unsubstituted C 3 ⁇ alkynylene, substituted or unsubstituted C ⁇ salkynylene, or substituted or unsubstituted Cs ⁇ alkynylene.
  • L 1 comprises at least one instance of substituted or unsubstituted heteroalkylene, e.g., substituted or unsubstituted heteroC ⁇ alkylene, substituted or unsubstituted heteroC i_ 2 alkylene, substituted or unsubstituted heteroC 2 _ 3 alkylene, substituted or unsubstituted heteroC 3 ⁇ alkylene, substituted or unsubstituted heteroC 4 _ salkylene, or substituted or unsubstituted heteroCs_ 6 alkylene.
  • substituted or unsubstituted heteroalkylene e.g., substituted or unsubstituted heteroC ⁇ alkylene, substituted or unsubstituted heteroC i_ 2 alkylene, substituted or unsubstituted heteroC 2 _ 3 alkylene, substituted or unsubstituted heteroC 3 ⁇ alkylene, substituted or unsubstituted heteroC 4 _ salkylene, or substituted or
  • L comprises at least one instance of substituted or unsubstituted heteroalkenylene, e.g., substituted or unsubstituted heteroC 2 - 6 alkenylene, substituted or unsubstituted heteroC 2 - 3 alkenylene, substituted or unsubstituted heteroC 3 _ 4 alkenylene, substituted or unsubstituted heteroC 4 _ 5 alkenylene, or substituted or unsubstituted heteroC 5 _ 6 alkenylene .
  • substituted or unsubstituted heteroalkenylene e.g., substituted or unsubstituted heteroC 2 - 6 alkenylene, substituted or unsubstituted heteroC 2 - 3 alkenylene, substituted or unsubstituted heteroC 3 _ 4 alkenylene, substituted or unsubstituted heteroC 4 _ 5 alkenylene, or substituted or unsubstituted heteroC 5 _ 6 alkenylene
  • L 1 comprises at least one instance of substituted or unsubstituted heteroalkynylene, e.g., substituted or unsubstituted heteroC 2 - 6 alkynylene, substituted or unsubstituted heteroC 2 - 3 alkynylene, substituted or unsubstituted heteroC 3 _ 4 alkynylene, substituted or unsubstituted heteroC ⁇ alkynylene, or substituted or unsubstituted heteroC 5 _ 6 alkynylene .
  • substituted or unsubstituted heteroalkynylene e.g., substituted or unsubstituted heteroC 2 - 6 alkynylene, substituted or unsubstituted heteroC 2 - 3 alkynylene, substituted or unsubstituted heteroC 3 _ 4 alkynylene, substituted or unsubstituted heteroC ⁇ alkynylene, or substituted or unsubstituted heteroC 5 _ 6
  • L 1 comprises at least one instance of substituted or unsubstituted carbocyclylene, e.g., substituted or unsubstituted C3_6carbocyclylene, substituted or unsubstituted C 3 ⁇ carbocyclylene, substituted or unsubstituted C ⁇ s
  • L 1 comprises at least one instance of substituted or unsubstituted heterocyclylene, e.g., substituted or unsubstituted 3-6 membered
  • heterocyclylene substituted or unsubstituted 3-4 membered heterocyclylene, substituted or unsubstituted 4-5 membered heterocyclylene, or substituted or unsubstituted 5-6 membered heterocyclylene.
  • L 1 comprises at least one instance of substituted or unsubstituted arylene, e.g., substituted or unsubstituted phenylene.
  • L 1 comprises at least one instance of substituted or unsubstituted heteroarylene, e.g., substituted or unsubstituted 5- to 6-membered
  • L 1 is a linker that contains an asymmetric
  • the compound comprising such an L 1 group is
  • the compound comprising such an L 1 group is racemic.
  • L 1 is a linker group as defined herein comprising at least one instance of any one of the following divalent moieties:
  • n is independently an integer between 1 to 10, inclusive;
  • each instance of m is independently 0, 1, or 2;
  • each instance of Q is independently -NR W1 -; -NR W1 -NR W1 -; -0-NR wl -;-NR wl -0- ; -S-; or -0-;
  • each instance of W is independently O, S, or NR W1 ;
  • each instance of G 3 and G 4 are independently N or CH;
  • each instance of R wl is independently hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; a nitrogen protecting group if attached to a nitrogen atom, or an oxygen protecting group if attached to an oxygen atom; each instance of R W2 is independently hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or two R W2 groups are joined to form
  • each instance of R W3 is independently hydrogen; halogen; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl, or two R W3 groups are joined to form a 3-6 membered ring;
  • n of any of the below formulae is independently an inte er between 1 to 10, inclusive, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10:
  • each instance of R is independently hydrogen; halogen; or substituted or unsubstituted alkyl (e.g., methyl).
  • m of any of the below formulae is independently 0, 1, or
  • G 3 and G 4 are independently N or CH:
  • m is 0, and R W3 is absent. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, G 3 is N. In certain embodiments, G 3 is CH. In certain embodiments, G 4 is N. In certain embodiments, G 4 is CH. In certain embodiments,
  • G 3 is N and G 4 is CH. In certain embodiments, G 3 is CH and G 4 is CH. In certain embodiments, G 3 is N and G 4 is N. In certain embodiments, G 3 is CH and G 4 is N. In certain embodiments, each instance of R W3 is independently hydrogen; halogen; or substituted or unsubstituted alkyl (e.g., methyl).
  • each instance of Q of any of the below formulae is independently -NR W1 -; -NR W1 -NR W1 -; -0-NR wl -;-NR wl -0-; -S-; or -0-, and each instance of W of any of the below formulae is independently O, S, or NR
  • Q is -NR W1 - In certain embodiments, Q is -NR W1 -NR W1 - In certain embodiments, Q is -0-NR wl - In certain embodiments, Q is -NR WL -0- In certain embodiments, Q is -S-. In certain embodiments, Q is -0-. In certain embodiments, W is O. In certain embodiments, W is S. In certain embodiments, W is NR W1 . In certain embodiments, W is O and Q is independently - S-, -NR W1 -, or -0-. In certain embodiments, R wl is not hydrogen. In certain embodiments, R wl is not hydrogen.
  • R W2 is hydrogen or substituted or unsubstituted alkyl (e methyl).
  • each instance of R wl is independently hydrogen
  • substituted or unsubstituted alkyl substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; a nitrogen protecting group if attached to a nitrogen atom, or an oxygen protecting group if attached to an oxygen atom.
  • each instance of R wl is independently hydrogen; substituted or unsubstituted alkyl (e methyl); a nitrogen protecting group if attached to a nitrogen atom, or an oxygen protecting group if attached to an oxygen atom.
  • each instance of R W2 is independently hydrogen
  • R W2 substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or two R W2 groups are joined to form a 5-6 membered ring.
  • each instance of R W2 is independently hydrogen or substituted or unsubstituted alkyl (e methyl).
  • each instance of R is independently hydrogen; halogen; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl, or two R W3 groups are joined to form a 3-6 membered ring.
  • each instance of R W3 is independently hydrogen; halogen; substituted or unsubstituted alkyl (e.g., methyl).
  • L 1 is a linker group as defined herein comprising one of the following divalent moieties directly (covalently) attached to the parent molecule:
  • L 1 is a linker comprising a combination of 1 to 20 consecutive covalently bonded divalent moieties described herein, e.g., 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 8 to 20, 9 to 20, 10 to 20, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, or 2 to 5 divalent moieties, inclusive.
  • L 1 is a linker comprising a combination of 2 to 6 consecutive covalently bonded divalent moieties, inclusive.
  • L 1 is a linker comprising a combination of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive covalently bonded divalent moieties.
  • L 1 is a linker comprising a combination of 4 consecutive covalently bonded divalent moieties.
  • L 1 is a linker 4 to 20 consecutive covalently bonded atoms in length, inclusive, e.g., 4 to 19, 4 to 18, 4 to 17, 4 to 16, 4 to 15, 4 to 14, 4 to 13, 4 to
  • L 1 is a linker 4, 5, 6, 7, 8, 9, 10, 11, 12,
  • L 1 is a linker 5, 6, 7, 8, 9, 10, 11,12, 13, 14, or 15 consecutive covalently bonded atoms in length.
  • L 1 is a linker group as defined herein comprising one of the followin divalent moieties directly (covalently) attached to the parent molecule:
  • L is a linker group as defined herein comprising one of the following divalent moieties directly (covalently) attached to the parent molecule:
  • n is an integer between 1 to 10, inclusive, and wherein R is as defined herein. In certain embodiments, n is 1, 2, or 3.
  • L 1 is a linker group as defined herein comprising one of the following divalent moieties directly (covalently) attached to the parent molecule:
  • -I ⁇ -R 11 represents a group of the formula
  • R H is a hydrophobic group selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aralkyl, substituted and
  • hydrophobic in the context of a “hydrophobic" group -R H , refers to a group -R which comprises zero hydrogen bond donors (e.g., no hydrogen attached to a nitrogen, oxygen, or sulfur, e.g., -NH 2 , -NH-, -OH, and/or -SH) and optionally zero hydrogen bond acceptors (e.g., no nitrogen, oxygen, or sulfur atoms).
  • zero hydrogen bond donors e.g., no hydrogen attached to a nitrogen, oxygen, or sulfur, e.g., -NH 2 , -NH-, -OH, and/or -SH
  • optionally zero hydrogen bond acceptors e.g., no nitrogen, oxygen, or sulfur atoms
  • a hydrophobic group comprises zero hydrogen bond. In certain embodiments, a hydrophobic group comprises zero hydrogen bond acceptors. In certain embodiments, a hydrophobic group comprises zero hydrogen bond donors and zero hydrogen bond acceptors.
  • a hydrophobic group is an unsubstituted hydrocarbon (carbocyclylalkyl, carbocyclyl, aralkyl, or aryl) group, e.g., comprising only carbon and hydrogen atoms.
  • a hydrophobic group comprises at least 6 carbon atoms, e.g., between 6 and 50 carbon atoms, between 6 and 40 carbon atoms, between 6 and 30 carbon atoms, between 6 and 20 carbon atoms, or between 6 and 15 carbon atoms, inclusive. In certain embodiments, a hydrophobic group comprises 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
  • R H is a hydrophobic, substituted or unsubstituted aryl; or a hydrophobic, substituted or unsubstituted aralkyl.
  • R is a hydrophobic, substituted or unsubstituted aryl moiety, e.g., substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, or substituted or unsubstituted anthracenyl.
  • R is a hydrophobic, substituted or unsubstituted aralkyl, wherein each instance of the arylene portion is independently substituted or unsubstituted 6- to 14-membered arylene.
  • R is a hydrophobic, substituted or unsubstituted arylmethyl, e.g. , substituted or unsubstituted benzyl, substituted or unsubstituted diphenylmethyl, substituted or unsubstituted trityl, substituted or unsubstituted biphenylmethyl, substituted or unsubstituted naphthylmethyl, or substituted or unsubstituted anthracenylmethyl.
  • R H is a hydrophobic moiety of the formula:
  • each occurrence of R and R is independently halogen, -CN, substituted or unsubstituted C 1-6 alkyl, -OR Hla , or -N(R Hla ) 2 , wherein each instance of R Hla is
  • each of p and q is independently 0, 1, 2, or 3.
  • each occurrence of R H1 and R H2 is independently halogen (e.g., fluoro, bromo, iodo, chloro), substituted or unsubstituted alkyl (e.g., methyl, ethyl, propyl, isopropyl, tertbutyl, difluoromethyl, perfluoromethyl), substituted hydroxyl (e.g., methoxy, ethoxy, isopropoxy), or disubstituted amino (e.g., dimethylamino, or diethylamino).
  • p is 0 or 1.
  • q is 0 or 1.
  • p is 0.
  • q is 0.
  • q is 0.
  • p is 0, and q is 0.
  • R is a hydrophobic moiety of the formula:
  • each occurrence of R , R , and R is independently halogen, -CN, substituted or unsubstituted C 1-6 alkyl, -OR Hla , or -N(R Hla ) 2 , wherein each instance of R Hla is
  • each of p, q, and r is independently 0, 1, 2, or 3.
  • each occurrence of R H1 , R m , and R ro is
  • halogen e.g., fluoro, bromo, iodo, chloro
  • substituted or unsubstituted alkyl e.g., methyl, ethyl, propyl, isopropyl, tertbutyl, difluoromethyl, perfluoromethyl
  • substituted hydroxyl e.g., methoxy, ethoxy, isopropoxy
  • disubstituted amino e.g., dimethylamino, or diethylamino.
  • R H is hydrophobic, substituted or unsubstituted heteroaryl; or hydrophobic, substituted or unsubstituted heteroarylalkyl.
  • R is hydrophobic, substituted or unsubstituted heteroaryl, e.g., substituted or unsubstituted, 5- or 6-membered monocyclic heteroaryl.
  • R is hydrophobic, substituted or unsubstituted heteroarylaralkyl, e.g., substituted or unsubstituted heteroarylmethyl, wherein each instance of the heteroarylene portion is independently a substituted or unsubstituted, 5- or 6-membered heteroarylene, wherein one, two, or three atoms in the heteroarylene ring system are independently nitrogen, oxygen, or sulfur.
  • R H is hydrophobic, substituted or unsubstituted carbocyclyl; or hydrophobic, substituted or unsubstituted carbocycylalkyl.
  • R is hydrophobic, substituted or unsubstituted carbocyclyl which may be monocyclic; fused, bridged, or spiro bicyclic; or fused, bridged, or spiro tricyclic.
  • R is substituted or unsubstituted .gcarbocyclyl, substituted or unsubstituted C3- 8 carbocyclyl, substituted or unsubstituted C3_ 7 carbocyclyl, substituted or unsubstituted C 3 _ 6 carbocyclyl, substituted or unsubstituted C 3 _ 5 carbocyclyl, or substituted or unsubstituted C 3 _ 4 carbocyclyl.
  • R is a hydrophobic, substituted or unsubstituted fused bicyclic carbocyclyl, e.g., substituted or unsubstituted cis- or iraws-decalin.
  • R is a hydrophobic, substituted or unsubstituted fused tricyclic carbocyclyl, e.g., substituted or unsubstituted fluorenyl.
  • R is a hydrophobic, substituted or unsubstituted spiro bicyclic carbocyclyl, e.g., substituted or unsubstituted spiropentanyl.
  • R is a hydrophobic, substituted or unsubstituted bridged bicyclic carbocyclyl, e.g., substituted or unsubstituted norbornanyl, norbornenyl, bicyclo[2.2.2]octanyl, a bicyclo[2.2.2]oct-2-ene radical, bicyclo[3.2.1]octanyl, or a bicyclo[2.2.1]heptan-2-one radical.
  • R is hydrophobic, substituted or unsubstituted, bridged, tricyclic carbocyclyl, e.g., substituted or unsubstituted adamantanyl.
  • R is hydrophobic, substituted or unsubstituted carbocycylalkyl, e.g., hydrophobic, substituted or unsubstituted carbocycylmethyl.
  • R H is a hydrophobic moiety of the formula:
  • each occurrence of R HI and R H2 is independently halogen, -CN, substituted or unsubstituted C 1-6 alkyl, -OR Hla , or -N(R Hla ) 2 , wherein each instance of R Hla is
  • each of p and q is independently 0, 1, 2, or 3.
  • each occurrence of R H1 and R H2 is independently halogen (e.g., fluoro, bromo, iodo, chloro), substituted or unsubstituted alkyl (e.g., methyl, ethyl, propyl, isopropyl, tertbutyl, difluoromethyl, perfluoromethyl), substituted hydroxyl (e.g., methoxy, ethoxy, isopropoxy), or disubstituted amino (e.g., dimethylamino, or diethylamino).
  • p is 0 or 1.
  • q is 0 or 1.
  • p is 0.
  • q is 0.
  • q is 0.
  • R is a hydrophobic moiety of the formula
  • each occurrence of R and R is independently halogen, -CN, substituted or unsubstituted C 1-6 alkyl, -OR Hla , or -N(R Hla ) 2 , wherein each instance of R Hla is
  • each of p and q is independently 0, 1, 2, or 3.
  • each occurrence of R H1 and R H2 is independently halogen (e.g., fluoro, bromo, iodo, chloro), substituted or unsubstituted alkyl (e.g., methyl, ethyl, propyl, isopropyl, tertbutyl, difluoromethyl, perfluoromethyl), substituted hydroxyl (e.g., methoxy, ethoxy, isopropoxy), or disubstituted amino (e.g., dimethylamino, or diethylamino).
  • p is 0 or 1.
  • q is 0 or 1.
  • p is 0.
  • R is hydrophobic, substituted or unsubstituted heterocyclyl or hydrophobic, substituted or unsubstituted heterocyclylalkyl.
  • R is a hydrophobic, substituted or unsubstituted heterocyclyl moiety, e.g., 4- 14-membered heterocyclyl which may be monocyclic heterocyclyl; fused, bridged, or spiro bicyclic heterocyclyl; or fused, bridged, or spiro tricyclic heterocyclyl.
  • R is hydrophobic, substituted or unsubstituted, 4- to 7-membered, monocyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are
  • R is hydrophobic, substituted or unsubstituted, 5- to 12-membered, bicyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are
  • R is hydrophobic, substituted or unsubstituted, 6- to 14-membered, tricyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are
  • R H is hydrophobic, substituted or unsubstituted heterocyclylalkyl.
  • the alkyl portion of the heterocyclylalkyl is C 1-6 alkyl.
  • R is hydrophobic, substituted or unsubstituted
  • heterocyclylmethyl In certain embodiments, the heterocyclic portion of the heterocyclylalkyl is substituted or unsubstituted, 4- to 7-membered, monocyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, the heterocyclic portion of the heterocyclylalkyl is substituted or unsubstituted, 5- to 12-membered, bicyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are
  • heterocyclic portion of the heterocyclylalkyl is substituted or unsubstituted, 6- to 14-membered, tricyclic heterocyclyl, wherein one, two, or three atoms in the
  • heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • R H is a hydrophobic moiety of the formula:
  • each occurrence of R HI and R H2 is independently halogen, -CN, substituted or unsubstituted C 1-6 alkyl, -OR , or -N(R ) 2 , wherein each instance of R ma is independently substituted or unsubstituted C 1-6 alkyl; and each of p and q is independently 0,
  • each occurrence of R HI and R H2 is independently fluoro, bromo, iodo, chloro, methyl, ethyl, propyl, isopropyl, tertbutyl, difluoromethyl,
  • p is 0 or 1.
  • q is 0 or 1.
  • p is 0.
  • q is 0.
  • p is 0, and q is 0.
  • molecular weight of a compound of Formula (I) or Formula (II) refers to the molecular weight of a compound described herein minus the combined molecular weight of any counterions, solvents, and water included with the compound (for example, when the compound is a salt ⁇ e.g., a pharmaceutically acceptable salt)).
  • the molecular weight of the hydrophobic group -R H may be between 50 and
  • the molecular weight of the hydrophobic moiety -R is between 100 and 200 g/mol, inclusive. It is understood that the molecular weight of the moiety R is calculated by subtracting 1 from the molecular weight of the compound H-R .
  • the molecular weight of the group -L'-R 11 may be between 50 and 600 g/mol, inclusive, e.g., between 50 and 500, between 100 and 500, between 100 and 400, between 100 and 300, between 100 and 200, between 200 and 400, or between 200 and 300 g/mol, inclusive.
  • the molecular weight of the moiety -L 1 -R H is between 200 and 300 g/mol, inclusive. It is understood that the molecular weight of the moiety -L 1 -
  • R is calculated by subtracting 1 from the molecular weight of the compound H-L -R .
  • the molecular weight of a compound of Formula (I) or Formula (II) may be between 400 and 1000 g/mol, inclusive, e.g., between 400 and 900, between 400 and 800, between 400 and 700, between 400 and 600, between 400 and 500, between 500 and 1000, between 500 and 900, between 500 and 800, or between 600 and 800 g/mol, inclusive. In certain embodiments, the molecular weight of a compound of Formula (I) is between 500 and 900 g/mol, inclusive. In certain embodiments, the molecular weight of a compound of Formula (I) or Formula (II) is between 600 and 900 g/mol, inclusive. In certain
  • the molecular weight of a compound of Formula (I) or Formula (II) is between 200 and 600 g/mol, inclusive.
  • the Log(partition coefficient) (LogP) of a compound described herein may be less than or equal to (at most) 5, e.g., between -8 to about 5, inclusive. In certain
  • LogP is determined by a shake flask (or shake tube) method using ultraviolet- visible spectroscopy.
  • a compound of Formula (I) or Formula (II) may consist of 0, 1, 2, 3, 4, 5, 6,
  • a compound of Formula (I) or Formula (II) may consist of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hydrogen bond acceptors, e.g., 3, 4, or 5 hydrogen bond acceptors.
  • a compound described herein is a compound of Formula la):
  • L is substituted or unsubstituted heteroCi-ealkylene or a substituted or unsubstituted C ⁇ alkylene.
  • L is . In certain embodiments, L is . In certain embodiments, each instance of n is independently 1, 2, 3, or 4. In
  • At least two instances of R A are F. In certain embodiments, at least two instances of R A are CI. In certain embodiments, at least one instance of R A is unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of R A is substituted C 1-6 alkyl. In certain embodiments, at least one instance of R A is -CH 3 . In certain embodiments, at least one instance of R A is -CF . In certain embodiments, R G is hydrogen. In certain embodiments, R G is -CH . In certain embodiments, R x is hydrogen. In certain embodiments, R x is -CN. In certain embodiments, R X is -OR XI . In certain embodiments, R X is -OR XI ; and R XI is -CH 3 .
  • R X is -OR XI ; and R XI is an oxygen protecting group.
  • R X is F.
  • RX is CI.
  • R X is Br.
  • R X is I (iodine).
  • R X is unsubstituted Ci_6 alkyl.
  • R X is substituted C 1-6 alkyl. In certain embodiments, R X is C 1-6 alkyl substituted with at least one halogen. In certain embodiments, R is -CH 3 . In certain embodiments, R is -CF . In certain embodiments, G 5 is S. In certain embodiments, G 5 is
  • NR E ; and RE is hydrogen.
  • G 5 is NR E ; and RE is -CH .
  • both R J1 and R J2 are hydrogen.
  • R J1 is hydrogen; and R is substituted or unsubstituted Ci-ealkyl.
  • R is hydrogen; and R is -CH .
  • a is 0. In certain embodiments, a is 1. In certain
  • each of R D2 and R D3 is hydrogen, and R D1 is -CH . In certain embodiments, each of R D1 and R D2 is hydrogen, and R D3 is -CH 2 N(R Dla ) 2 . In certain embodiments, each of
  • R D1 and R D2 is hydrogen, and R D3 is -CH 2 0R Dla . In certain embodiments, each of R D1 and R D2 is hydrogen, and R D3 is -CH 2 0R Dla . In certain embodiments, each of R D1 and R D2 is hydrogen, and R D3 is -CH 2 0R Dla . In certain embodiments, each of R D1 and R D2 is hydrogen, and R D3 is -CH 2 0R Dla . In certain embodiments, each of R D1 and
  • R D2 is hydrogen
  • R D3 is -CH 2 N(R Dla ) 2
  • R Dla is hydrogen
  • R D1 and R D2 is hydrogen, R D3 is -CH 2 N(R Dla ) 2 , and R Dla is methyl.
  • each of R D1 and R D2 is hydrogen, R D3 is -CH 2 OR Dla , and R Dla is hydrogen.
  • each of R D1 and R D2 is hydrogen, R D3 is -CH 2 OR Dla , and R Dla is methyl.
  • R D4 is hydrogen.
  • R D4 is substituted or unsubstituted alkyl.
  • R m is a nitrogen protecting group. In certain embodiments, the group is attached meta to the point of attachment
  • the group is attached para to the point of attachment
  • a compound of Formula (la) is a compound of
  • L 1 is substituted or unsubstituted heteroC ⁇ ealk lene or a substituted or unsubstituted C ⁇ alkylene.
  • L is or . In certain embodiments, L is certain embodiments, each instance of n is independently 1, 2, 3, or 4. In
  • R is ln certain embodiments, q is 0. [00317]
  • a compound of Formula (la) is a compound of
  • L is substituted or unsubstituted heteroCi-ealkylene or a substituted or unsubstituted Ci ⁇ alkylene.
  • L 1 is or In certain embodiments, L 1 is . In certain embodiments, each instance of n is independently 1, 2, 3, or 4. In
  • q is 0.
  • a compound of Formula (la) wherein R A hydrogen grou is a compound of Formula (Ia-3):
  • L 1 is substituted or unsubstituted heteroCi-ealkylene or a substituted or unsubstituted Ci ⁇ alkylene.
  • the group R D R is attached meta to the point of
  • the group is attached para to the
  • each instance of n is independently 1,
  • q is 0.
  • L 1 is substituted or unsubstituted heteroCi-ealk lene or a substituted or unsubstituted Ci ⁇ alkylene.
  • L is or . In certain embodiments, L is . In certain embodiments, the group is attached meta to the point of
  • the group is attached para to the
  • each instance of n is independently 1,
  • R is , or
  • q is 0.
  • a compound of Formula (la) wherein R A is a non- hydrogen grou is a compound of Formula (Ia-5):
  • L 1 is substituted or unsubstituted heteroCi-ealk lene or a substituted or unsubstituted Ci ⁇ alkylene.
  • the group is attached meta to the point of attachment . In certain embodiments, the group is attached para to the
  • each instance of n is independently 1,
  • R is or
  • q is 0.
  • a compound of Formula (la) wherein R A is a non- hydrogen group is a compound of Formula (Ia-6):
  • L 1 is substituted or unsubstituted heteroCi-ealk lene or a substituted or unsubstituted Ci ⁇ alkylene.
  • the group is attached meta to the point of
  • n is independently 1,
  • R is , or
  • q is 0.
  • a compound of Formula (la) is a compound of
  • L is substituted or unsubstituted heteroCi-ealk lene or a substituted or unsubstituted Ci ⁇ alkylene.
  • L is .
  • the group is attached meta to the point of
  • the group is attached para to the
  • each instance of n is independently 1,
  • a compound of Formula (la) is a compound of
  • a compound of Formula (la) is a compound of
  • R is .
  • q is 0.
  • a compound of Formula (la) is a compound of
  • R is .
  • q is 0.
  • a compound of Formula (la) is a compound of
  • R is or a phar maceutically acceptable salt thereof.
  • R is or a phar maceutically acceptable salt thereof.
  • R is or a phar maceutically acceptable salt thereof.
  • R is or a phar maceutically acceptable salt thereof.
  • R is or a phar maceutically acceptable salt thereof.
  • R is or a phar maceutically acceptable salt thereof.
  • R is or a phar maceutically acceptable salt thereof.
  • q is 0.
  • a compound of Formula (la) is a compound of
  • R is .
  • q is 0.
  • a compound of Formula (la) is a compound of
  • R is .
  • q is 0.
  • a compound of Formula (la) is a compound of
  • L is substituted or unsubstituted heteroCi-ealk lene or a substituted or unsubstituted Ci ⁇ alkylene.
  • L is or . In certain embodiments, L is In certain embodiments, each instance of n is independently 1, 2, 3, or 4. In certain embodiments, a compound of Formula (la) is a compound of
  • L 1 is substituted or unsubstituted heteroCi-ealk lene or a substituted or unsubstituted Ci ⁇ alkylene.
  • L is or . i n certain embodiments, L is . In certain embodiments, each instance of n is independently 1, 2, 3, or 4.
  • a compound described herein is a compound of
  • L is substituted or unsubstituted heteroC alkylene or a substituted or unsubstituted C ⁇ alkylene.
  • L is or . In certain embodiments, L is . In certain embodiments, each instance of n is independently 1, 2, 3, or 4. In
  • R H is ( Rh1 ) q . (R H1 ) q ; ( rH ⁇ or " (rH V In certain embodiments, q is 0. In certain embodiments, k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, at least one instance of R A is halogen. In certain embodiments, at least one instance of R A is F. In certain embodiments, at least one instance of R A is CI. In certain embodiments, at least two instances of R A are independently halogen. In certain embodiments, at least two instances of R A are F. In certain embodiments, at least two instances of R A are CI.
  • At least one instance of R A is unsubstituted C 1-6 alkyl. In certain embodiments, at least one instance of R A is substituted d- 6 alkyl. In certain embodiments, at least one instance of R A is -CH 3 . In certain embodiments, at least one instance of R A is -CF . In certain embodiments, R G is hydrogen. In certain embodiments, R G is -CH 3 . In certain embodiments, R x is hydrogen. In certain embodiments,
  • R X is -CN. In certain embodiments, R X is -OR XI . In certain embodiments, R X is -OR XI ; and
  • R XI is -CH . In certain embodiments, R X is -OR XI ; and R XI is an oxygen protecting group. In certain embodiments, R X is F. In certain embodiments, RX is CI. In certain embodiments, R X is Br. In certain embodiments, R X is I (iodine). In certain embodiments, R X is unsubstituted
  • R X is substituted C 1-6 alkyl. In certain embodiments, R X -6 a is Ci_6 alkyl substituted with at least one halogen. In certain embodiments, R is -CH . In certain embodiments, R is -CF . In certain embodiments, G 5 is S. In certain embodiments,
  • each of R D2 and R D3 is hydrogen, and R D1 is -CH 3 .
  • each of R D1 and R D2 is hydrogen, and R D3 is -CH 2 N(R Dla ) 2 .
  • each of R D1 and R D2 is hydrogen, and R D3 is -CH 2 OR Dla .
  • each of R D1 and R D2 is hydrogen, R D3 is -CH 2 N(R Dla ) 2
  • R Dla is hydrogen.
  • each of R D1 and R D2 is hydrogen, R D3 is -CH 2 N(R Dla ) 2 , and R Dla is methyl.
  • each of R D1 and R D2 is hydrogen, R D3 is -CH 2 OR Dla , and R Dla is hydrogen. In certain embodiments, each of R D1 and R D2 is hydrogen, R D3 is -CH 2 OR Dla , and R Dla is methyl. In certain embodiments, R D4 is hydrogen. In certain embodiments, R D4 is substituted or unsubstituted alkyl. In certain embodiments, R m is a nitrogen protecting group. In certain
  • the group is attached meta to the point of attachment
  • a compound of Formula (lb) is a compound of
  • L is substituted or unsubstituted heteroCi-ealkylene or a substituted or unsubstituted Ci ⁇ alkylene.
  • L is . In certain embodiments, L is certain embodiments, R is or In certain embodiments, q is 0.
  • a compound of Formula (lb) is a compound of
  • L 1 is substituted or unsubstituted heteroC ⁇ alk lene or a substituted or
  • i nstance of n is independently 1, 2, 3, or 4.
  • R is
  • a compound of Formula (lb) wherein R is a non- hydrogen group is a com ound of Formula (Ib-3):
  • the group attached meta to the point of attachment In certain embodiments,
  • L is substituted or unsubstituted heteroCi-ealk lene or a substituted or
  • i nstance of n is independently 1, 2, 3, or 4.
  • R is
  • a compound of Formula (lb) wherein R is a non- hydrogen group is a com ound of Formula (Ib-4):
  • the group attached meta to the point of attachment In certain embodiments,
  • L 1 is substituted or unsubstituted heteroC ⁇ alk lene or a substituted or
  • i nstance of n is independently 1, 2, 3, or 4. In certain embodiments, R i
  • a compound of Formula (lb) wherein R is a non- hydrogen group is a com ound of Formula (Ib-5):
  • the group s a tached meta to the point of attachment In certain embodiments,
  • L 1 is substituted or unsubstituted heteroCi-ealkylene or a substituted or unsubstituted Q_
  • L is In certain embodiments,
  • each instance of n is independently
  • a compound of Formula (lb) wherein R A is a non- hydrogen group is a compound of Formula (Ib-6):
  • the group attached meta to the point of attachment In certain embodiments,
  • L 1 is substituted or unsubstituted heteroC ⁇ alk lene or a substituted or
  • i nstance of n is independently 1, 2, 3, or 4.
  • R is
  • a compound of Formula (lb) is a compound of
  • the group attached meta to the point of attachment In certain embodiments,
  • L is substituted or unsubstituted heteroC ⁇ alk lene or a substituted or
  • i nstance of n is independently 1, 2, 3, or 4. In certain embodiments, R i
  • a compound of Formula (lb) is a compound of
  • R is substituted or ain embodiments, R is
  • q is 0.
  • a compound of Formula (lb) is a compound of
  • R is substituted or ain embodiments, R is
  • a compound of Formula (lb) is a compound of
  • R is substituted or ain embodiments, R is
  • q is 0.
  • a compound of Formula (lb) is a compound of
  • R is substituted or ain embodiments, R is
  • a compound of Formula (lb) is a compound of
  • a compound of Formula (lb) is a compound of
  • R is substituted or unsubstituted adamantyl. In certain embodiments, or *> ⁇ C vR H1 1 q j n certain embodiments, q is 0.
  • a compound of Formula (lb) is a compound of
  • L 1 is substituted or unsubstituted heteroCi-ealk lene or a substituted or unsubstituted Ci ⁇ alkylene.
  • L is In certain embodiments, L is certain embodiments, each instance of n is independently 1, 2, 3, or 4. In certain embodiments, a compound of Formula (lb) is a compound of
  • L is substituted or unsubstituted heteroC ⁇ alk lene or a substituted or
  • n is independently 1, 2, 3, or 4.
  • a compound described herein is a compound of
  • L 1 is substituted or unsubstituted heteroC _ 6 alkylene or a substituted or unsubstituted C ⁇ alkylene.
  • L is or . In certain embodiments, L is In certain embodiments, each instance of n is independently 1, 2, 3, or 4. In
  • q is 0. In certain embodiments, k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, at least one instance of R A is halogen. In certain embodiments, at least one instance of R A is F. In certain embodiments, at least one instance of R A is CI. In certain embodiments, at least two instances of R A are independently halogen. In certain embodiments, at least two instances of R A are F. In certain embodiments, at least two instances of R A are CI. In certain embodiments, at least one instance of R A is unsubstituted C 1-6 alkyl. In certain embodiments, at least one instance of R A is substituted d- 6 alkyl.
  • At least one instance of R A is -CH 3 . In certain embodiments, at least one instance of R A is -CF . In certain embodiments, R G is hydrogen. In certain embodiments, R G is -CH . In certain embodiments, R x is hydrogen. In certain embodiments,
  • R X is -CN. In certain embodiments, R X is -OR XI . In certain embodiments, R X is -OR XI ; and
  • R XI is -CH 3 . In certain embodiments, R X is -OR XI ; and R XI is an oxygen protecting group. In certain embodiments, R X is F. In certain embodiments, RX is CI. In certain embodiments, R X is Br. In certain embodiments, R X is I (iodine). In certain embodiments, R X is unsubstituted
  • Ci X iments, R X - 6 alkyl In certain embodiments, R is substituted Ci_ 6 alkyl. In certain embod is Ci- 6 alkyl substituted with at least one halogen. In certain embodiments, R is -CH 3 . In certain embodiments, R is -CF . In certain embodiments, G 5 is S. In certain embodiments,
  • G 5 is NR E ; and RE is hydrogen. In certain embodiments, G 5 is NR E ; and RE is -CH . In certain embodiments, both R J1 and R J2 are hydrogen. In certain embodiments, R J1 is hydrogen; and R is substituted or unsubstituted Ci_ 6 alkyl. In certain embodiments, R is hydrogen; and R is -CH . In certain embodiments, a is 0. In certain embodiments, a is 1. In certain
  • each of R , R , and R is hydrogen. In certain embodiments, each of R D2 and R D3 is hydrogen, and R D1 is -CH 3 . In certain embodiments, each of R D1 and R D2 is hydrogen, and R D3 is -CH 2 N(R Dla ) 2 . In certain embodiments, each of R D1 and R D2 is hydrogen, and R D3 is -CH 2 0R Dla .
  • each of R D1 and R D2 is hydrogen, R D3 is -CH 2 N(R Dla ) 2 , and R Dla is hydrogen. In certain embodiments, each of R D1 and R D2 is hydrogen, R D3 is -CH 2 N(R Dla ) 2 , and R Dla is methyl. In certain embodiments, each of R D1 and R D2 is hydrogen, R D3 is -CH 2 OR Dla , and R Dla is hydrogen. In certain embodiments, each of R D1 and R D2 is hydrogen, R D3 is -CH 2 OR Dla , and R Dla is methyl. In certain embodiments, R D4 is hydrogen. In certain embodiments, R D4 is substituted or unsubstituted
  • the group is attached para to the point of attachment
  • the group R is -L - R , as defined herein.
  • a compound described herein is a compound of the formula:
  • a compound described herein is a compound of Formula Ila):
  • L 1 is substituted or unsubstituted heteroCi-ealk lene or a substituted or unsubstituted C ⁇ alkylene.
  • L 1 is In certain embodiments, L 1 is
  • R A is unsubstituted C 1-6 alkyl. In certain embodiments, at least one instance of R A is substituted C 1-6 alkyl. In certain embodiments, at least one instance of R A is -CH 3 . In certain embodiments, at least one instance of R A is -CF 3 . In certain embodiments, R G is hydrogen. In certain embodiments, R G is -CH . In certain embodiments, R x is hydrogen. In certain embodiments, R X is -CN. In certain embodiments, R X is -OR XI . In certain embodiments, all instances of R are hydrogen. In certain embodiments, L is an unsubstituted C ⁇ alkylene. In certain embodiments, at least one instance of R A is unsubstituted C 1-6 alkyl. In certain embodiments, at least one instance of R A is substituted C 1-6 alkyl. In certain embodiments, at least one instance of R A is -CH 3 . In certain embodiments, at least one instance of R A is -
  • R x is -OR xl ; and R xl is -CH 3 .
  • R x is -OR xl ; and R xl is an oxygen protecting group.
  • R X is F.
  • R X is CI.
  • R X is Br.
  • R X is I (iodine).
  • R X is unsubstituted C 1-6 alkyl.
  • R X is substituted C 1-6 alkyl.
  • R is C 1-6 alkyl substituted with at least one halogen.
  • R is -CH 3 .
  • R is -CF .
  • G 5 is S.
  • G 5 is NR E ; and R E is hydrogen.
  • G 5 is NR E ; and RE is -CH 3 .
  • both R Jl and R J 2 are hydrogen.
  • R Jl is hydrogen; and R J 2 is substituted or unsubstituted Ci_
  • R Jl is hydrogen; and R J2 is -CH .
  • R D3 is hydrogen. In certain embodiments, each of R D2 and R D3 is hydrogen, and R Dl is -CH . In certain embodiments, each of R D1 and R D2 is hydrogen, and R D3 is -CH 2 N(R Dla ) 2 . In certain embodiments, each of R D1 and R D2 is hydrogen, and R D3 is -CH 2 0R Dla . In certain embodiments, each of R D1 and R D2 is hydrogen, R D3 is -CH 2 N(R Dla ) 2 , and R Dla is hydrogen. In certain embodiments, each of R D1 and R D2 is hydrogen, R D3 is -CH 2 N(R Dla ) 2 , and R Dla is methyl.
  • each of R D1 and R D2 is hydrogen, R D3 is -CH 2 OR Dla , and R Dla is hydrogen. In certain embodiments, each of R D1 and R D2 is hydrogen, R D3 is - CH 2 OR Dla , and R Dla is methyl. In certain embodiments, R m is hydrogen. In certain embodiments, R D4 is substituted or unsubstituted alkyl. In certain embodiments, R D4 is a
  • the group is attached meta
  • the group is
  • a compound of Formula (Ila) is a compound of
  • L 1 is substituted or unsubstituted heteroCi-ealkylene or a substituted or unsubstituted Ci ⁇ alkylene.
  • L 1 is or In certain embodiments, L is certain embodiments, each instance of n is independently 1, 2, 3, or 4. In
  • R is ln certain embodiments, q is 0.
  • a compound of Formula (Ila) is a compound of
  • L is substituted or unsubstituted heteroC ⁇ ealkylene or a substituted or unsubstituted C ⁇ alkylene. In certain embodiments, L is or . In certain embodiments, L is . In certain embodiments, each instance of n is independently 1, 2, 3, or 4. In
  • q is 0.
  • a compound of Formula (Ila) is a compound of
  • L 1 is substituted or unsubstituted heteroC ⁇ ealk lene or a substituted or unsubstituted C ⁇ alkylene.
  • L is .
  • L is certain embodiments, each instance of n is independently 1, 2, 3, or 4.
  • q is 0.
  • a compound of Formula (Ila) is a compound of
  • L is substituted or unsubstituted heteroC ⁇ ealkylene or a substituted or unsubstituted C ⁇ alkylene.
  • L is or . In certain embodiments, L is
  • R is or ln certain embodiments, q is 0.
  • a compound of Formula (Ila) is a compound of
  • the group attached meta to the point of attachment In certain embodiments,
  • L 1 is substituted or unsubstituted heteroC ⁇ alk lene or a substituted or
  • i nstance of n is independently 1, 2, 3, or 4.
  • R is
  • q is 0.
  • a compound of Formula (Ila) is a compound of
  • L is substituted or unsubstituted heteroCi-ealkylene or a substituted or unsubstituted Ci ⁇ alkylene.
  • L is . In certain embodiments, L 1 is In certain embodiments, each instance of n is independently 1, 2, 3, or 4. In
  • R n is
  • q is 0.
  • a compound of Formula (Ila) is a compound of
  • L 1 is substituted or unsubstituted heteroCi-ealkylene or a substituted or unsubstituted C ⁇ alkylene.
  • L is or In certain embodiments, L is . In certain embodiments, each instance of n is independently 1, 2, 3, or 4. In
  • a compound of Formula (Ila) is a compound of
  • R is substituted or unsubstituted adamantyl. In certain embodiments, R is
  • q is 0.
  • a compound of Formula (Ila) is a compound of
  • R is substituted or unsubstituted adamantyl. In certain embodiments, R is . In certain embodiments, q is 0.
  • a compound of Formula (Ila) is a compound of
  • R is
  • q is 0.
  • a compound of Formula (Ila) is a compound of
  • R is substituted or In certain embodiments, q is 0.
  • a compound of Formula (Ila) is a compound of

Abstract

La présente invention concerne des inhibiteurs de la Janus kinase, tels que des composés de formule (I) et de formule (II) dans lesquelles RY1 et RY2 comprennent une fraction hydrophobe marquée RH. Les composés peuvent se lier de manière covalente ou non covalente à une kinase (par exemple, à la Janus kinase 3 TT (JAK3)). La fraction hydrophobe R peut envoyer un signal à la machinerie de l'homéostasie des protéines intracellulaires destiné à induire une dégradation de la kinase ciblée. L'invention concerne également des compositions pharmaceutiques, des kits, des méthodes et des utilisations impliquant ces composés et destinés à réduire l'activité d'une kinase et/ou à traiter et/ou à prévenir un état associé à une activité aberrante d'une kinase (par exemple, une maladie proliférative, un trouble inflammatoire, un trouble auto-immun, un état douloureux et/ou une infection virale).
PCT/US2015/027294 2014-04-23 2015-04-23 Inhibiteurs de janus kinase marqués de manière hydrophobe et utilisations associées WO2015164604A1 (fr)

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